Cephem compounds

ABSTRACT

This invention relates to new cephem compounds of antimicrobial activity, of the formula: ##STR1## wherein R 1  is amino or a protected amino group; 
     R 2  is hydrogen, lower aliphatic hydrocarbon group which may be substituted with suitable substituent(s), cyclo(lower)alkyl or cyclo(lower)alkenyl; and 
     R 3  is thiazolio group which may be substituted with suitable substituent(s) or a pyridinio group substituted with substituent(s) selected from the group consisting of halogen, cyano, hydroxy, amino, acylamino, lower alkanoyl, hydroxycarbamoyl, alkylcarbamoyl, carboxy, protected carboxy, lower alkyl, hydroxy(lower)alkyl, sulfo(lower)alkyl, protected amino(lower)alkyl, amino(lower)alkyl, carboxy(lower)alkyl and hydroxyimino(lower)alkyl; and pharmaceutically acceptable salts thereof.

The present invention relates to new cephem compounds andpharmaceutically acceptable salts thereof. More particularly, it relatesto new cephem compounds and pharmaceutically acceptable salts thereof,which have antimicrobial activities and to processes for preparationthereof, to pharmaceutical composition comprising the same, and to amethod of using the same therapeutically in the treatment of infectiousdiseases in humans being and animals.

Accordingly, it is one object of the present invention to provide newcephem compounds and pharmaceutically acceptable salts thereof, whichare active against a number of pathogenic microorganisms.

Another object of the present invention is to provide processes for thepreparation of new cephem compounds and pharmaceutically acceptablesalts thereof.

A further object of the present invention is to provide pharmaceuticalcomposition comprising, as active ingredients, said new cephem compoundsand pharmaceutically acceptable salts thereof.

Still further object of the present invention is to provide a method forthe treatment of infectious diseases caused by pathogenic bacteria inhuman being and animals.

The object new cephem compounds are novel and can be represented by thefollowing general formula (I). ##STR2## wherein R¹ is amino or aprotected amino group;

R² is hydrogen, lower aliphatic hydrocarbon group which may besubstituted with suitable substituent(s), cyclo(lower)alkyl orcyclo(lower)alkenyl; and

R³ is a thiazolio group which may be substituted with suitablesubstituent(s) or a pyridinio group substituted with substituent(s)selected from the group consisting of halogen, cyano, hydroxy, amino,acylamino, lower alkanoyl, hydroxycarbamoyl, alkylcarbamoyl, carboxy,protected carboxy, lower alkyl, hydroxy(lower)alkyl,sulfo(lower)alkyl,protected amino(lower)alkyl, amino(lower)alkyl, carboxy(lower)alkyl andhydroxyimino(lower)alkyl.

According to the present invention, the new cephem compounds (I) can beprepared by various processes which are illustrated in the followingscheme. ##STR3## wherein R¹, R² and R³ are each as defined above;

R⁴ is a group which can be substituted with a group of the formula: R³wherein R³ is as defined above;

R^(3a) is thiazole which may be substituted with suitable substituent(s)or pyridine substituted with substituent(s) selected from the groupconsisting of halogen, cyano, hydroxy, acylamino, lower alkanoyl,hydroxycarbamoyl, alkylcarbamoyl, carboxy, protected carboxy, loweralkyl, hydroxy(lower)alkyl, sulfo(lower)alkyl, protectedamino(lower)alkyl, amino(lower)alkyl, carboxy(lower)alkyl andhydroxyimino(lower)alkyl;

R^(3b) is a pyridinio group substituted with protectedamino(lower)alkyl;

R^(3c) is a pyridinio group substituted with amino(lower)alkyl;

R^(2a) is protected carboxy(lower)alkyl;

R^(2b) is carboxy(lower)alkyl;

R⁵ is a protected carboxy group; and

X is an acid residue.

Among the starting compounds of the present invention, the compound (VI)is novel and can be prepared by the following methods. ##STR4## whereinR¹, R², R³, R^(3a), R⁵ and X are each as defined above.

Regarding the object compounds (I), (Ia), (Ib), (Ic) and (Id) and thestarting compounds (II), (V), (VIII), (VI), (IX) and (X), it is to beunderstood that said object and starting compounds include syn isomer,anti isomer and a mixture thereof. For example, with regard to theobject compound (I), syn isomer means one geometrical isomer having thepartial structure represented by the following formula: ##STR5##(wherein R¹ and R² are each as defined above) and anti isomer means theother geometrical isomer having the partial structure represented by thefollowing formula: ##STR6## (wherein R¹ and R² are each as definedabove).

Regarding the other object compounds and statring compounds as mentionedabove, the syn isomer and the anti isomer can also be referred to thesame geometrical isomers as illustrated for the compound (I).

Suitable pharmaceutically acceptable salts of the object compounds (I)are conventional non-toxic salt and include a metal salt such as analkali metal salt (e.g. sodium salt, potassium salt, etc.) and analkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), anammonium salt, an organic base salt (e.g. trimethylamine salt,triethylamine salt, pyridine salt, picoline salt, dicyclohexylaminesalt, N,N'-dibenzylethylenediamine salt, etc.), an organic acid salt(e.g. acetate, maleate, tartrate, methanesulfonate, benzenesulfonate,formate, toluenesulfonate, etc.), an inorganic acid salt (e.g.hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.), ora salt with an amino acid (e.g. arginine, aspartic acid, glutamic acid,etc.), and the like.

In the above and subsequent descriptions of the present specification,suitable examples and illustrations of the various definitions which thepresent invention include within the scope thereof are explained indetails as follows.

The term "lower" is intended to mean 1 to 6 carbon atoms, unlessotherwise indicated.

Suitable "protected amino" for R¹ and "protected amino" moiety in theterm "protected amino(lower)alkyl" may include an acylamino or an aminogroup substituted by a conventional protecting group such asar(lower)alkyl which may have at least one suitable substituent(s),(e.g. benzyl, trityl, etc.) or the like.

Suitable acyl moiety in the term "acylamino" may include carbamoyl,aliphatic acyl group and acyl group containing an aromatic orheterocyclic ring. And, suitable examples of the said acyl may be loweralkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, oxalyl, succinyl, pivaloyl, etc.); lower alkoxycarbonylhaving 2 to 7 carbon atoms (e.g. methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, tertiarybutoxycarbonyl, pentyloxycarbonyl,hexyloxycarbonyl, etc.); lower alkanesulfonyl (e.g. mesyl,ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl,etc.); arenesulfonyl (e.g. benzenesulfonyl, tosyl, etc.); aroyl (e.g.benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, indancarbonyl, etc.);ar(lower)alkanoyl (e.g. phenylacetyl, phenylpropionyl, etc.);ar(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl,etc.), and the like. The acyl moiety as stated above may have at leastone suitable substituent(s) such as halogen (chlorine, bromine, fluorineand iodine), lower alkanoyl or the like.

Suitable lower aliphatic hydrocarbon group may include lower alkyl,lower alkenyl, lower alkynyl and the like.

Suitable "cyclo(lower)alkyl" for R² may include one having 3 to 6 carbonatoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orthe like, preferably one having 4 to 6 carbon atoms.

Suitable "cyclo(lower)alkenyl" for R² may include one having 3 to 6carbon atoms, for example, cyclopentenyl, cyclohexenyl or the like,preferably one having 5 to 6 carbon atoms.

Suitable "lower alkyl" and "lower alkyl" moiety in the terms"hydroxy(lower)alkyl", "sulfo(lower)alkyl", "protectedamino(lower)alkyl", "hydroxyimino(lower)alkyl", "amino(lower)alkyl","protected carboxy(lower)alkyl" and "carboxy(lower)alkyl" is one having1 to 6 carbon atom(s) and may include methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tert-butyl, pentyl, tert-pentyl, hexyl and the like,and preferably one having 1 to 4 carbon atom(s).

Suitable "lower alkenyl" is one having 2 to 6 carbon atoms and mayinclude vinyl, allyl, isopropenyl, 1-propenyl, 2-butenyl, 3-pentenyl andthe like.

Suitable "lower alkynyl" is one having 2 to 6 carbon atoms and mayinclude ethynyl, 2-propynyl, 2-butynyl, 3-pentynyl, 3-hexynyl and thelike.

The lower aliphatic hydrocarbon group as mentioned above may besubstituted with 1 to 3 suitable substituent(s) such as carboxy,protected carboxy as mentioned below, halogen (e.g. chlorine, bromine,etc.) or the like.

Suitable substituent(s) on a thiazolio group for R³ and thiazole forR^(3a) may include lower alkyl (e.g. methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tert-butyl, pentyl, tert-pentyl, hexyl, etc.),hydroxy(lower)alkyl (e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl,hydroxybutyl, etc.) and the like, and the number of the substituent(s)may be 1 to 3.

A pyridinio group for R³ or pyridine for R^(3a) is substituted with 1 to3 substituent(s) as mentioned above.

Suitable "halogen" may include chlorine, bromine, fluorine and iodine.

Suitable "lower alkanoyl" can be referred to the ones as exemplified foraforesaid "acyl".

Suitable "alkyl" moiety in the term "alkylcarbamoyl" is one having 1 to14 carbon atom(s) and may include methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl, t-pentyl, hexyl, heptyl, octyl, nonyl,decyl, undecyl, dodecyl, tridecyl, tetradecyl and the like, preferablyone having 1 to 12 carbon atom(s).

Suitable "protected carboxy" and "protected carboxy" moiety in the term"protected carboxy(lower)alkyl" may include esterified carboxy in whichsaid ester may be the ones such as alkyl ester (e.g. methyl ester, ethylester, propyl ester, isopropyl ester, butyl ester, isobutyl ester,t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, heptyl ester,octyl ester, nonyl ester, decyl ester, undecyl ester, dodecyl ester,hexadecyl ester, etc.);

lower alkenyl ester (e.g. vinyl ester, allyl ester, etc.); lower alkynylester (e.g. ethynyl ester, propynyl ester, etc.); mono(or di ortri)-halo(lower)alkyl ester (e.g., 2-iodoethyl ester,2,2,2-trichloroethyl ester, etc.); lower alkanoyloxy(lower)alkyl ester(e.g. acetoxymethyl ester, propionyloxymethyl ester, 1-acetoxypropylester, valeryloxymethyl ester, pivaloyloxymethyl ester,hexanoyloxymethyl ester, 1-acetoxyethyl ester, 2-propionyloxyethylester, 1-isobutyryloxyethyl ester, etc.); loweralkanesulfonyl(lower)alkyl ester (e.g., mesylmethyl ester, 2-mesylethylester, etc.); ar(lower)alkyl ester, for example, phenyl(lower)alkylester which may be substituted with one or more suitable substituent(s)(e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester,phenethyl ester, trityl ester, diphenylmethyl ester,bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester,4-hydroxy-3,5-ditertiarybutylbenzyl ester, etc.); loweralkoxycarbonyloxy(lower)alkyl ester (e.g. methoxycarbonyloxymethylester, ethoxycarbonyloxymethyl ester, ethoxycarbonyloxyethyl ester,etc.) which may be substituted with azido; a heterocyclic ester,preferably benzotetrahydrofuryl ester which may be substituted with oxogroup, more preferably phthalidyl ester; aroyloxy(lower)alkyl ester(e.g. benzoyloxymethyl ester, benzoyloxyethyl ester, toluoyloxyethylester, etc.); aryl ester which may have one or more suitablesubstituent(s) (e.g. phenyl ester, tolyl ester, tertiarybutylphenylester, xylyl ester, mesityl ester, cumenyl ester, etc.), and the like.Preferable example of "protected carboxy" may be alkoxycarbonyl (e.g.methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl,heptyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl,undecyloxycarbonyl, dodecyloxycarbonyl, hexadecyloxycarbonyl, etc.).

Suitable R⁴ may include an acid residue such as acyloxy, azido, halogenor the like, wherein acyl moiety in the term "acyloxy" and halogen canbe referred to the ones as exemplified above.

Suitable X may include acid residue as above.

Preferred embodiments of the object compound (I) are as follows:

Preferred embodiment of R¹ is amino; R² is lower alkyl (most preferablyethyl), cyclo(lower)alkyl (most preferably cyclopentyl),cyclo(lower)alkenyl (most preferably cyclopentenyl), carboxy(lower)alkylor esterified carboxy(lower)alkyl (more preferably loweralkoxycarbonyl(lower)alkyl); R³ is thiazolio, thiazolio substituted withlower alkyl and hydroxy(lower)alkyl, or pyridinio substituted with 1 to2 substituent(s) selected from the group consisting of halogen, cyano,hydroxy, lower alkanoyl (most preferably acetyl), acylamino (morepreferably lower alkanesulfonylamino, most preferably mesylamino),amino, hydroxycarbamoyl, alkylcarbamoyl, carboxy, alkoxycarbonyl, loweralkyl, hydroxy(lower)alkyl, carboxy(lower)alkyl, amino(lower)alkyl,lower alkoxycarbonylamino(lower)alkyl, sulfo(lower)alkyl andhydroxyimino(lower)alkyl.

The processes for preparing the object compounds of the presentinvention are explained in details in the following.

Process 1

The object compound (I) or a salt thereof can be prepared by reactingthe compound (II) or a salt thereof with the compound (III).

Suitable salt of the compound (II) can be referred to the onesexemplified for the compound (I).

The present reaction may be carried out in a solvent such as water,phosphate buffer, acetone, chloroform, acetonitrile, nitrobenzene,methylene chloride, ethylene chloride, formamide, dimethylformamide,methanol, ethanol, ether, tetrahydrofuran, dimethylsulfoxide, or anyother organic solvent which does not adversely affect the reaction,preferably in ones having strong polarities. Among the solvents,hydrophilic solvents may be used in a mixture with water. The reactionis preferably carried out in around neutral medium. When the compounds(II) is used in a free form, the reaction is preferably conducted in thepresence of a base, for example, inorganic base such as alkali metalhydroxide, alkali metal carbonate, alkali metal bicarbonate, organicbase such as trialkylamine, and the like. The reaction temperature isnot critical, and the reaction is usually carried out at ambienttemperature, under warming or under heating. The present reaction ispreferably carried out in the presence of alkali metal halide (e.g.sodium iodide, potassium iodide, etc.), alkali metal thiocyanate (e.g.sodium thiocyanate, potassium thiocyanate, etc.) etc.

Process 2

The object compound (Ib) or a salt thereof can be prepared by subjectingthe compound (Ia) or a salt thereof to elimination reaction of theprotective group of amino.

Suitable salts of the compounds (Ia) and (Ib) can be referred to theones exemplified for the compound (I).

The present elimination reaction is carried out in accordance with aconventional method such as hydrolysis; reduction; a method by reactingthe compound (Ia) wherein the protective group is acyl group withiminohalogenating agent and then with iminoetherifying agent, and, ifnecessary, subjecting the resulting compound to hydrolysis; or the like.The hydrolysis may include a method using an acid or base or hydrazineand the like. These methods may be selected depending on the kind of theprotective groups to be eliminated.

Among these methods, hydrolysis using an acid is one of the common andpreferable method for eliminating the protective group such assubstituted or unsubstituted alkoxycarbonyl (e.g. t-pentyloxycarbonyl,t-butoxycarbonyl, etc.), alkanoyl (e.g. formyl, etc.),cycloalkoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl (e.g.benzyloxycarbonyl, substituted benzyloxycarbonyl, etc.), ar(lower)alkyl(e.g. benzyl, trityl, etc.) or the like.

Suitable acid may include an organic or an inorganic acid, for example,formic acid, trifluoroacetic acid, benzenesulfonic acid,p-toluenesulfonic acid, hydrochloric acid and the like, and preferableacid is, for example, formic acid, trifluoroacetic acid, hydrochloricacid, etc. The acid suitable for the reaction can be selected accordingto the kind of protective group to be eliminated. When the eliminationreaction is conducted with the acid, it can be carried out in thepresence or absence of a solvent. Suitable solvent may include aconventional organic solvent, water or a mixture thereof. Whentrifluoroacetic acid is ued, the elimination reaction may preferably becarried out in the presence of anisole.

The hydrolysis using hydrazine is commonly applied for eliminating theprotective group, for example, succinyl or phthaloyl.

The hydrolysis with a base is preferably applied for eliminating acylgroup, for example, haloalkanoyl (e.g. dichloroacetyl, trifluoroacetyl,etc.) etc. Suitable base may include, for example, an inorganic basesuch as alkali metal hydroxide (e.g. sodium hydroxide, potassiumhydroxide, etc.), alkaline earth metal hydroxide (e.g. magnesiumhydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.g. sodiumcarbonate, potassium carbonate, etc.), alkaline earth metal carbonate(e.g. magnesium carbonate, calcium carbonate, etc.), alkali metalbicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.),alkali metal acetate (e.g. sodium acetate, potassium acetate, etc.),alkaline earth metal phosphate (e.g. magnesium phosphate, calciumphosphate, etc.), alkali metal hydrogen phosphate (e.g. disodiumhydrogen phosphate, dipotassium hydrogen phosphate, etc.), or the like,and an organic base such as trialkylamine (e.g. trimethylamine,triethylamine, etc.), picoline, N-methylpyrrolidine, N-methylmorpholine,1,5-diazabicyclo[4,3,0]non-5-ene, 1,4-diazabicyclo[2,2,2]octane,1,5-diazabicyclo[5,4,0]undecene-5 or the like. The hydrolysis using abase is often carried out in water, a conventional organic solvent or amixture thereof.

Among the protective group, the acyl group can be generally eliminatedby hydrolysis as mentioned above or by the other conventionalhydrolysis. In case that the acyl group is halogensubstituted-alkoxycarbonyl or 8-quinolyloxycarbonyl, they are eliminatedby treating with a heavy metal such as copper, zinc or the like.

The reductive elimination is generally applied for eliminating theprotective group, for example, haloalkoxycarbonyl (e.g.trichloroethoxycarbonyl, etc.), substituted or unsubstitutedaralkoxycarbonyl (e.g. benzyloxycarbonyl, substituted benzyloxycarbonyletc.), 2-pyridylmethoxycarbonyl, etc. Suitable reduction may include,for example, reduction with an alkali metal borohydride (e.g. sodiumborohydride, etc.) and the like.

The reaction temperature is not critical and may be suitably selected inaccordance with the kind of the protective group of the amino group andthe elimination method as mentioned above, and the present reaction ispreferably carried out under a mild condition such as under cooling, atambient temperature or slightly elevated temperature.

The present reaction includes, within its scope, the cases that theprotected amino group for R¹ is transformed into the free amino group inthe course of the elimination reaction as mentioned above or in thepost-treatment of the reaction mixture of reaction product.

Process 3

The object compound (I) or a salt thereof can be prepared by reactingthe compound (IV) or its reactive derivative at the amino group or asalt thereof with the compound (V) or its reactive derivative at thecarboxy group or a salt thereof.

Suitable reactive derivative at the amino group of the compound (IV) mayinclude conventional reactive derivative used in amidation, for example,Schiff's base type imino or its tautomeric enamine type isomer formed bythe reaction of the compound (IV) with a carbonyl compound; a silylderivative formed by the reaction of the compound (IV) with a silylcompound such as bis(trimethylsilyl)acetamide, trimethylsilylacetamideor the like; a derivative formed by reaction of the compound (IV) withphosphorus trichloride or phosgene, and the like.

Suitable salt of the compound (IV) may include an acid addition saltsuch as an organic acid salt (e.g. acetate, maleate, tartrate,benzenesulfonate, toluenesulfonate, etc.) or an inorganic acid salt(e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.); a metalsalt (e.g. sodium salt, potassium salt, calcium salt, magnesium salt,etc.); ammonium salt; an organic amine salt (e.g. triethylamine salt,dicyclohexylamine salt, etc.), and the like.

Suitable reactive derivative at the carboxy group of the compound (V)may include an acid halide, an acid anhydride, an activated amide, anactivated ester, and the like. The suitable example may be an acidchloride; an acid azide; a mixed acid anhydride with an acid such assubstituted phosphoric acid (e.g. dialkylphosphoric acid,phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid,halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurousacid, thiosulfuric acid, sulfuric acid, alkylcarbonic acid, aliphaticcarboxylic acid (e.g. pivalic acid, pentanoic acid, isopentanoic acid,

2-ethylbutyric acid, acetic acid or trichloroacetic acid, etc.) oraromatic carboxylic acid (e.g. benzoic acid, etc.); a symmetrical acidanhydride; an activated amide with imidazole, dimethylpyrazole, triazoleor tetrazole; or an activated ester (e.g. cyanomethyl ester,methoxymethyl ester, dimethyliminomethyl [(CH₃)₂ N⁺ =CH--] ester, vinylester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester,trichlorophenyl ester, pentachlorophenyl ester, mesyl phenyl ester,phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester,p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridylester, piperidyl ester, 8-quinolyl thioester, or an ester withN,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone,N-hydroxysuccinimide, N-hydroxyphthalimide or1-hydroxy-6-chloro-1H-benzotriazole, and the like. These reactivederivatives can be optionally selected from them according to the kindof the compound (V) to be used.

The salts of the compound (V) may be salts with an inorganic base suchas an alkali metal salts (e.g. sodium or potassium salt), or an alkalineearth metal salt (e.g. calcium or magnesium salt), a salt with anorganic base such as trimethylamine, triethylamine, pyridine, a saltwith an acid (e.g. hydrochloric acid or hydrobromic acid) or the like.

The reaction is usually carried out in a conventional solvent such aswater, acetone, dioxane, acetonitrile, chloroform, methylene chloride,ethylene chloride, tetrahydrofuran, ethyl acetate,N,N-dimethylformamide, pyridine or any other organic solvent which doesnot adversely influence to the reaction. Among these solvents,hydrophilic solvents may be used in a mixture with water.

When the compound (V) is used in free acid form or its salt form in thereaction, the reaction is preferably carried out in the presence of aconventional condensing agent such as N,N-dicyclohexylcarbodiimide;N-cyclohexyl-N'-morpholinoethylcarbodiimide;N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide;N,N-diethylcarbodiimide; N,N,diisopropylcarbodiimide;N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;N,N-carbonylbis(2-methylimidazole);pentamethylene-ketene-N-cyclohexylimine;diphenylketene-N-cyclohexylimine; ethoxyacetylene; ethyl polyphosphate;isopropyl polyphosphate; diethyl phosphorochloridite; phosphorusoxychloride; phosphorus trichloride; phosphorus pentachloride; thionylchloride; oxalyl chloride; triphenylphosphine;N-ethyl-7-hydroxybenzisoxazolium fluoroborate;N-ethyl-5-phenylisoxazolium-3'-sulfonate;1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-calledVilsmeier reagent, for example (chloromethylene) dimethylammoniumchloride produced by the reaction of dimethylformamide with thionylchloride or phosgene, a compound produced by the reaction ofdimethylformamide with phosphorus oxychloride, etc.; or the like.

The reaction may be also carried out in the presence of an inorganic oran organic base such as an alkali metal hydroxide, an alkali metalbicarbonate, alkali metal carbonate, alkali metal acetate,tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine,N,N-di(lower)alkylbenzylamine, N,N-di(lower)alkylaniline as exemplifiedbelow, or the like. When the base or the condensing agent is in liquid,it can be used also as a solvent. The reaction temperature is notcritical, and the reaction is usually carried out under cooling or atambient temperature.

In the present reaction, a syn-isomer of the object compound (I) can beobtained preferably by conducting the reaction of the compound (IV) witha synisomer of the starting compound (V).

Process 4

The object compound (Id) or a salt thereof can be prepared by subjectingthe compound (Ic) or a salt thereof to elimination reaction of theprotective group of carboxy.

Suitable salt of the compounds (Ic) and (Id) can be referred to the onesexemplified for the compound (I).

The present reaction is carried out in accordance with a conventionalmethod such as hydrolysis, reduction or the like.

In case that the protective group is an ester, the protective group canbe eliminated by hydrolysis. Hydrolysis is preferably carried out in thepresence of a base or an acid. Suitable base may include an inorganicbase and an organic base such as an alkali metal (e.g. sodium,potassium, etc.), an alkaline earth metal (e.g. magnesium, calcium,etc.), the hydroxide or carbonate or bicarbonate thereof, trialkylamine(e.g. trimethylamine, triethylamine, etc.), picoline,1,5-diazabicyclo[4,3,0]none-5-ene, 1,4-diazabicyclo[2,2,2]octane,1,8-diazabicyclo[5,4,0]undecene-7, or the like. Suitable acid mayinclude an organic acid (e.g. formic acid, acetic acid, propionic acid,trifluoroacetic acid, etc.) and an inorganic acid (e.g. hydrochloricacid, hydrobromic acid, sulfuric acid, etc.).

The reaction is usually carried out in a solvent such as water, analcohol (e.g. methanol, ethanol, etc.), a mixture thereof or any othersolvent which does not adversely influence to the reaction. A liquidbase or acid can be also used as the solvent. The reaction temperatureis not critical and the reaction is usually carried out under cooling towarming.

Reduction can be applied preferably for elimination of the protectivegroup such as 4-nitrobenzyl, 2-iodoethyl, 2,2,2-trichloroethyl, or thelike. The reduction method applicable for the elimination reaction mayinclude, for example, reduction by using a combination of a metal (e.g.zinc, zinc amalgam, etc.) or a salt of chrome compound (e.g. chromouschloride, chromous acetate, etc.) and an organic or inorganic acid (e.g.acetic acid, propionic acid, hydrochloric acid. etc.); and conventionalcatalytic reduction in the presence of a conventional metallic catalyst(e.g. palladium-carbon, etc.).

Process 5

The compound (I) or a salt thereof can be prepared by subjecting thecompound (VI) to elimination reaction of carboxy-protective group.

The present elimination reaction can be carried out according to asimilar manner to that of Process 4.

The Preparations of the starting compound(VI) are explained in detail inthe following.

Preparation 1

The compound (VIII) can be prepared by reacting the compound (V) or itsreactive derivative at the carboxy group or a salt thereof with thecompound (VII) or its reactive derivative at the amino group or a saltthereof.

The present reaction can be carried out in a similar manner to that ofProcess 3.

Preparation 2

The compound (IX) or a salt thereof can be prepared by oxidizing thecompound (VIII) or a salt thereof.

Suitable oxidizing agent to be used in this reaction may include alloxidizing agent which can oxidize --S-- group in cephalosporin compoundsto ##STR7## group, for example, peroxide (e.g., hydrogen peroxide,3-chloroperbenzoic acid, etc.) and the like.

The reaction is usually carried out in solvent such as methylenechloride or any other solvent which does not adversely affect thereaction. The reaction temperature is not critical and preferably undercooling or at ambient temperature.

Preparation 3

The compound (X) can be prepared by reacting the compound (IX) or a saltthereof with the compound R^(3a).

The reaction can be carried out according to a similar manner to that ofProcess 1.

Preparation 4

The compound (VI) can be prepared by reducing the compound (X).

The present reduction can be carried out in the presence of conventionalreducing agent which can reduce ##STR8## group in cephalosporin compoundto --S-- group, for example, phosphorus halide such as phosphorustrihalide (e.g., phosphorus trichloride, etc.).

The object compound (I) of the present invention exhibits highantimicrobial activity and inhibits the growth of a number ofmicroorganisms including pathogenic Gram-positive and Gram-negativebacteria.

For therapeutic administration, the cephalosporin compounds according tothe present invention are used in the form of pharmaceutical preparationwhich contain said compounds in admixture with a pharmaceuticallyacceptable carriers such as an organic or inorganic solid or liquidexcipient suitable for oral, parenteral or external administration. Thepharmaceutical preparations may be in solid form such as capsule,tablet, dragee, ointment or suppository, or in liquid form such assolution, suspension, or emulsion. If desired, there may be included inthe above preparations auxiliary substances, stabilizing agents, wettingor emulsifying agents, buffers and other commonly used additives.

While the dosage of the compounds may vary from and also depend upon theage and condition of the patient, an average single dose of about 50mg., 100 mg., 250 mg., and 500 mg. of the compounds according to thepresent invention has proved to be effective for treating of infectiousdiseases caused by a number of pathogenic bacteria. In general amounts,daily dose between 1 mg/body and about 1000 mg/body or even more may beadministered.

Now in order to show the utility of the object compounds (I), test dataon anti-microbial activity of representative compounds of the presentinvention are shown below.

Test Method

One loopful of an overnight culture of each test strain inTrypticase-soy broth (10⁸ viable cells per ml.) was streaked on heartinfusion agar (HI-agar) containing graded concentrations of antibiotics,and the minimal inhibitory concentration (MIC) was expressed in terms ofμg/ml after incubation at 37° C. for 20 hours.

Test Compound

(1)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer)

(2)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer)

(3)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-chloro-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer)

(4)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3,5-dimethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer)

(5)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(3-hydroxypropyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate(syn isomer)

Test Results

    ______________________________________                                                   Test Compound MIC (μg/ml)                                       Test Bacteria                                                                              (1)     (2)     (3)   (4)   (5)                                  ______________________________________                                        B. subtilis ATCC 6633                                                                      0.78    0.78    0.78  1.56  0.78                                 Ps. aeruginosa 2                                                                           6.25    12.50   6.25  6.25  12.50                                S. marcescens 35                                                                           3.13    1.56    3.13  3.13  1.56                                 ______________________________________                                    

The following Preparations and Examples are given for the purpose ofillustrating the present invention.

Preparation 1

To a suspension of isonicotinoyl chloride hydrochloride (8.94 g) inmethylene chloride (50 ml) was dropped a solution of t-butylamine (11.0g) in methylene chloride (30 ml) over 70 minutes below 40° C. understirring. The mixture was stirred for 4 hours at ambient temperature andpoured into water. After the mixture was adjusted to pH 7.5 with aqueoussodium bicarbonate, the organic layer was separated out, washed withwater, dried over magnesium sulfate and evaporated to dryness to giveN-t-butylisonicotinamide (6.8 g), mp. 115° C. to 117° C.

IR (Nujol): 3270, 1638, 1595, 1544, 1317, 1210 cm⁻¹

NMR (DMSO-d₆, δ): 140 (9H, s), 7.7 (2H, m), 8.05 (1H, bs), 8.7 (2H, m)

Preparation 2

The following compounds were obtained according to a similar manner tothat of Preparation 1.

(1) N-Octylisonicotinamide, mp 61° to 63° C.

IR (Nujol): 3290, 1630, 1595, 1538, 1310, 1290 cm⁻¹

(2) N-Dodecylisonicotinamide, mp 71° to 74° C.

IR (Nujol): 3400, 3320, 1630, 1598, 1535 cm⁻¹

Preparation 3

A mixture of isonicotinoyl chloride hydrochloride (17.8 g),t-butylalcohol (14.8 g) and 4-(N,N-dimethylamino)pyridine (122 mg) inmethylene chloride (200 ml) was refluxed for 6 hours. The mixture waswashed with aqueous sodium bicarbonate and water, dried over magnesiumsulfate and evaporated to give oily t-butyl isonicotinate (8.3 g).

IR (film): 2950, 2830, 1720, 1580, 1560, 1410, 1365, 1320, 1290, 1145,1120 cm⁻¹

NMR (DMSO-d₆, δ): 1.42 (9H, s), 7.7 (2H, m), 8.7 (2H, m)

Preparation 4

A mixture of N-hydroxyphthalimide (58.2 g), 1-chloro-2-cyclopentene(36.9 g), triethylamine (53.9 g) in acetonitrile (370 ml) was stirred togive N-(2-cyclopenten-1-yloxy)phthalimide (56.5 g)

IR (Nujol): 1780, 1730, 1610 cm⁻¹

NMR (DMSO-d₆, δ): 7.92 (4H, s), 6.28 (1H, m), 6.00 (1H, m), 5.42 (1H,m), 2.9-1.98 (4H, m)

Preparation 5

(1) A mixture of N-(2-cyclopenten-1-yloxy)phthalimide (22.9 g) andhydrazine hydrate (4.75 g) in ethanol (115 ml) was refluxed for 5minutes. The reaction mixture was filtered. The filtrate containing(2-cyclopenten-1-yl)oxyamine was added to a solution of sodium2-(5-formamido-1,2,4-thiadiazol-3-yl)glyoxylate (22.4 g) in water. Themixture was adjusted to pH 2 with 10% hydrochloric acid, stirred for 2hours and then concentrated. The concentrate was adjusted to pH 1 with10% hydrochloric acid. The precipitates were collected by filtration anddried to give2-(2-cyclopenten-1-yl)oxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer) (20.0 g), mp 150° C. (dec.).

IR (Nujol): 3400, 3100, 1720, 1690, 1540 cm⁻¹

NMR (DMSO-d₆, δ): 1.80-2.50 (4H, m), 5.30-5.50 (1H, m), 5.83-6.30 (2H,m), 8.90 (1H, s)

(2) To a solution of sodium hydroxide (11.2 g) in water (140 ml) wasadded S-methyl 2-(5-formamido-1,2,4-thiadiazol-3-yl)thioglyoxylate (27g) at 10° C. and the mixture was stirred for 30 minutes at 20° C. Thereaction mixture containing sodium2-(5-formamido-1,2,4-thiadiazol-3-yl)glyoxylate was cooled, adjusted topH 7 with 10% hydrochloric acid and thereto was added a solution ofcyclopentyloxyamine (15.3 g) in ethanol (150 ml). The mixture wasadjusted to pH 3 with 10% hydrochloric acid, and stirred for 1.5 hours.The reaction mixture was adjusted to pH 7 with an aqueous solution ofsodium bicarbonate and then evaporated to remove ethanol. The residuewas washed with ethyl acetate. To the aqueous layer was added ethylacetate and the mixture was adjusted to pH 1 with 10% hydrochloric acid.The precipitates were collected by filtration to give2-cyclopentyloxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid(syn isomer) (3.99 g). The filtrate was extracted with ethyl acetate andthe extract was dried over magnesium sulfate and then concentrated. Theprecipitates were collected by filtration and washed with diethyl etherto give the same object compound (8.1 g). Total yield: 12.09 g, mp 180°to 185° C. (dec.).

IR (Nujol): 3130, 3040, 2680, 2610, 2520, 1720, 1690, 1660, 1600, 1550cm⁻¹

NMR (DMSO-d₆, δ): 1.33-2.10 (8H, m), 4.67-5.0 (1H, m), 8.88 (1H, s),13.50 (1H, s)

Preparation 6

A mixture of2-(2-cyclopenten-1-yl)oxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer) (20.0 g) and 1 N aqueous solution of sodium hydroxide(200 ml) was stirred for an hour at 50° to 55° C. The reaction mixturewas cooled, adjusted to pH 7 with 10% hydrochloric acid and thereto wasadded ethyl acetate. The mixture was adjusted to pH 1 with 10%hydrochloric acid and extracted with ethyl acetate. The extract waswashed with a saturated aqueous solution of sodium chloride, dried overmagnesium sulfate and evaporated. The residue was pulverized withdiisopropyl ether to give2-(2-cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp 150° C. (dec.).

IR (Nujol): 3300, 3150, 1710, 1620, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 1.80-2.50 (4H, m), 5.30-5.50 (1H, m), 5.83-6.30 (2H,m), 8.20 (2H, s)

Preparation 7

The following compound was obtained according to a similar manner tothat of Preparation 6.

2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (synisomer), mp 160° to 165° C. (dec.).

IR (Nujol): 3470, 3290, 3200, 2400, 1715, 1615, 1600, 1520 cm⁻¹

NMR (DMSO-d₆, δ) 1.17-2.10 (8H, m), 4.60-4.97 (1H, m), 8.22 (2H, s)

Preparation 8

A mixture of S-methyl(5-formamido-1,2,4-thiadiazol-3-yl)thioglyoxylate(6 g) and an aqueous solution (50 ml) of sodium hydroxide (4.2 g) wasstirred for an hour at 50° to 55° C. The mixture was cooled to ambienttemperature and adjusted to pH 7 with 10% hydrochloric acid. On theother hand, a mixture of N-(ethoxycarbonylmethoxy)phthalimide (12.9 g)and hydrazine hydrate (2.08 g) in ethanol (60 ml) was refluxed for 5minutes and cooled in an ice bath. A resulting precipitate was filteredoff and washed with ethanol. The filtrate and the washings were combinedand the combined solution containingO-(ethoxycarbonylmethyl)hydroxylamine was added to the above aqueoussolution. The mixture was adjusted to pH 3 to 4 with 10% hydrochloricacid and stirred for 1.5 hours at ambient temperature. The solution wasneutralized with an aqueous solution of sodium bicarbonate, concentratedto half volume in vacuo and washed with ethyl acetate. The aqueoussolution was acidified with 10% hydrochloric acid and extracted withethyl acetate. The extract was dried over magnesium sulfate, evaporatedto dryness and the residue was triturated with diisopropyl ether to give2-ethoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer) (1.8 g), mp 135° to 140° C. (dec.).

IR (Nujol): 3500,3330,3210,2670,2550,1740, 1610,1540 cm⁻¹

NMR (DMSO-d₆, δ): 1.24 (3H, t, J=7 Hz), 4.14 (2H, q, J=7 Hz), 4.80 (2H,s), 8.15 (2H, broad s)

Preparation 9

The following compounds were obtained according to a similar manner tothat of Preparation 8.

(1)2-(t-Butoxycarbonylmethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp 150° to 155° C. (dec.).

IR (Nujol): 3420, 3230, 3100, 1725, 1610, 1530 cm⁻¹

NMR (DMSO-d₆, δ): 1.45 (9H, s), 4.70 (2H, s), 8.12 (2H, broad s)

(2)2-(1-Ethoxycarbonyl-1-methylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp 165° to 168° C. (dec.).

IR (Nujol): 3450, 3350, 3240, 1750, 1730, 1630, 1530 cm⁻¹

NMR (DMSO-d₆, δ): 1.18 (3H, t, J=7 Hz), 1.50 (6H, s), 4.15 (2H, q, J=7Hz), 8.23 (2H, broad s)

Preparation 10

To a cold solution of phosphorus pentachloride (16.6 g) in methylenechloride (150 ml) was added2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer)(17.3 g) at -18° C. and the mixture was stirred for 15 minutes at -13°to -10° C. On the other hand, a mixture of7-amino-3-acetoacetoxymethyl-3-cephem-4-carboxylic acid (25.1 g) andtrimethylsilylacetamide (80 g) in methylene chloride (400 ml) was warmedto make a clear solution and cooled to -10° C. The cold solution wasadded to the above activated mixture and the mixture was stirred for 1hour at -10° C. The reaction mixture was poured into an aqueous solution(450 ml) of sodium bicarbonate (42 g) and stirred for 1 hour at roomtemperature. The aqueous layer was separated out, adjusted to pH 2 with6 N hydrochloric acid and extracted with ethyl acetate. The extract waswashed with water, dried over anhydrous magnesium sulfate and evaporatedto dryness. The residue was triturated with diethyl ether to give apowder of7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylicacid (syn isomer) (24.5 g). This compound was dissolved in 1 N methanolsolution of sodium acetate (48 ml) and stood on to give precipitates.Thereto was added acetone (100 ml). The precipitates were collected byfiltration, washed with acetone to give sodium7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylate(syn isomer) (19 g).

Physical constants of7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylicacid (syn isomer): mp 101° to 106° C. (dec.).

IR (Nujol): 3400, 3300, 3170, 1770, 1710, 1660, 1620, 1525, 1145, 1035cm⁻¹

Physical constants of sodium7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylate(syn isomer): mp 175° to 180° C. (dec.).

IR (Nujol): 3450, 3300, 3100, 1790, 1720, 1670, 1640, 1610, 1550 cm⁻¹

NMR (D₂ O, δ): 1.38 (3H, t, J=6 Hz), 2.34 (3H, s), 3.44, 3.66 (2H, ABq,J=18 Hz), 4.40 (2H, q, J=6 Hz), 5.05, 5.86 (2H, ABq, J=12 Hz), 5.26 (1H,d, J=4 Hz), 5.90 (1H, d, J=4 Hz)

Preparation 11

The following compounds were obtained according to a similar manner tothat of Preparation 10.

(1)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylicacid (syn isomer), powder, mp. 130° to 135° C. (dec.).

IR (Nujol): 3300, 1780, 1720, 1680, 1620, 1525 cm⁻¹

NMR (DMSO-d₆, δ): 1.3-2.0 (8H, m), 2.15 (3H, s), 3.52 (2H, bs), 3.60(2H, s), 4.5-4.7 (1H, m), 4.77, 5.00 (2H, ABq, J=14 Hz), 5.13 (1H, d,J=4 Hz), 5.80 (1H, 2d, J=4 and 8 Hz), 8.10 (2H, s), 9.50 (1H, d, J=8 Hz)

(2)7-[2-(2-Cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 135° to 140° C. (dec.).

IR (Nujol): 3400, 3300, 3200, 1775, 1735, 1710, 1675, 1620, 1525 cm⁻¹

NMR (DMSO-d₆, δ): 1.93-2.47 (4H, m), 2.18 (3H, s), 3.55 (2H, bs), 3.65(2H, s), 4.80, 5.07 (2H, ABq, J=13 Hz), 5.13 (1H, d, J=5 Hz), 5.23-5.53(1H, m), 5.70-6.23 (3H, m), 8.12 (2H, bs), 9.50 (1H, d, J=8 Hz)

(3)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 95° to 100° C. (dec.).

IR (Nujol): 3400, 3290, 3190, 1770, 1720, 1615, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 2.17 (3H, s), 3.53 (2H, bs), 3.63 (2H, s), 4.67 (2H,s), 4.80, 5.07 (2H, ABq, J=13 Hz), 5.15 (1H, d, J=5 Hz), 5.87 (1H, 2d,J=5 and 8 Hz) 8.15 (2H, bs), 9.53 (1H, d, J=8 Hz)

(4)7-[2-t-Butoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 105° to 110° C. (dec.).

IR (Nujol): 3350, 3250, 1780, 1720, 1620, 1525 cm⁻¹

NMR (DMSO-d₆, δ): 1.43 (9H, s), 2.17 (3H, s), 3.53 (2H, bs), 3.63 (2H,s), 4.63 (2H, s), 4.82, 5.05 (2H, ABq, J=13 Hz), 5.15 (1H, d, J=5 Hz),5.85 (1H, 2d, J=5 and 8 Hz), 8.15 (2H, bs), 9.53 (1H, d, J=8 Hz)

(5)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer). mp 140° to 145° C. (dec.).

IR (Nujol): 3480, 3370, 3250, 1785, 1730, 1680, 1630, 1530 cm⁻¹

NMR (DMSO-d₆, δ): 1.33-2.17 (8H, m), 2.03 (3H, s), 3.57 (2H, broad s),4.60-4.90 (1H, m), 4.73 and 4.97 (2H, ABq, J=13 Hz), 5.15 (1H, d, J=5Hz), 5.80 (1H, dd, J=5 and 8 Hz), 8.10 (2H, broad s), 9.47 (1H, d, J=8Hz)

(6)7-[2-(2-Cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer). mp 154° to 159° C. (dec.).

IR (Nujol): 3300, 1770, 1720, 1670, 1620, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 2.0 (3H, s), 2.0-2.40 (4H, m), 3.52 (2H, broad s),4.70 and 4.97 (2H, ABq, J=14 Hz), 5.12 (1H, d, J=4 Hz), 5.27-5.40 (1H,m), 5.82 (1H, dd, J=4 and 8 Hz), 5.83-6.17 (2H, m), 8.13 (2H, s), 9.50(1H, d, J=8 Hz)

(7)7-[2-(t-Butoxycarbonylmethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer), mp 125° to 130° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1720, 1680, 1620, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 1.50 (9H, s), 2.10 (3H, s), 3.62 (2H, broad s), 4.68(2H, s), 4.77 and 5.03 (2H, ABq, J=13 Hz), 5.20 (1H, d, J=4 Hz), 5.88(1H, dd, J=4 and 8 Hz), 8.18 (2H, s), 9.55 (1H, d, J=8 Hz)

(8)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer), mp 160° to 165° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1720, 1680, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 2.10 (3H, s), 3.60 (2H, broad s), 4.70 (2H, s), 4.77and 5.03 (2H, ABq, J=14 Hz), 5.20 (1H, d, J=4 Hz), 5.88 (1H, dd, J=4 and8 Hz), 8.18 (2H, s), 9.57 (1H, d, J=8 Hz)

Preparation 12

To a suspension of7-(2-thienyl)acetamido-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(27.0 g) and N,N-dimethylaniline (50.8 g) in methylene chloride (240 ml)was dropped trimethylsilyl chloride (26.0 g) under stirring and themixture was stirred for 1.5 hours at room temperature. To the resultingsolution was added phosphorous pentachloride (31.2 g) at -30° C. and themixture was stirred for one hour at -30° C. to -25° C. The mixture wasadded to a solution of n-butanol (120 g) in methylene chloride (240 ml)at -25° C. under stirring, and the stirring was continued for 1.5 hoursat room temperature. A resulting precipitate was collected byfiltration, washed with methylene chloride and dried on phosphorouspentoxide to give7-amino-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylatedihydrochloride (25.5 g), mp 120° to 125° C. (dec.).

IR (Nujol): 1780, 1700, 1630 cm⁻¹

NMR (DCl+D₂ O, δ); 3.60, 3.83 (2H, ABq, J=18 Hz), 4.97 (2H, s), 5.33(1H, d, J=5 Hz), 5.47 (1H, d, J=5 Hz), 5.60, 5.93 (2H, ABq, J=14 Hz),8.0-8.33 (1H, m), 8.50-8.76 (1H, m), 8.83-9.16 (2H, m)

EXAMPLE 1 ##STR9##

To a mixture of 3-hydroxymethylpyridine (26.6 g) and sodium iodide (150g) in formamide (240 ml) was added sodium7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-cephalosporanate(syn isomer) (60 g) by portions at 75° C. under stirring, which wascontinued for 3 hrs. at 80° to 85° C. The mixture was cooled to 20° C.and diluted with isopropyl alcohol (3 l) to give an oily substance,which was separated by decantation. The separated oily substance wastriturated in isopropyl alcohol (1 l) to give a crude object compound asa powder. The crude product was dissolved in water (500 ml) andsubjected to column chromatography on a non ionic adsorption resin"Diaion HP-20"(Trademark, prepared by Mitsubishi Chemical Industries)(1.8 l). After the Column was washed with water (5.5 l), the elution wascarried out with 30% aqueous methanol. The eluates (2.5 l) containing anobject compound were collected, concentrated to 550 ml under reducedpressure and passed through a column packed with acidic alumina (150 g).The eluate (700 ml) was lyophilized to give white powder of7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer) (12.5 g), mp 160° to 165° C.(dec.).

I.R. (Nujol): 3300, 1770, 1660, 1610, 1520 cm⁻¹

N.M.R. (D₂ O, δ): 1.23 (3H, t, J=7 Hz), 3.23 and 3.57 (2H, ABq, J=17Hz), 4.30 (2H, q, J=7 Hz), 4.83 (2H, s), 5.23 (1H, d, J=4 Hz), 5.33 and5.53 (2H, ABq, J=14 Hz), 5.85 (1H, d, J=4 Hz), 8.03 (1H, dd, J=6 and 8Hz), 8.50 (1H, d, J=8 Hz), 8.85 (1H, d, J=6 Hz), 8.90 (1H, s)

EXAMPLE 2 ##STR10##

To a mixture of 4-(2-sulfoethyl)pyridine (4.56 g), potassium thiocyanate(24 g) and sodium carbonate (1.3 g) in water (25 ml) was added sodium7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanate(syn isomer) (6.0 g) at 50° C. under stirring. The mixture was stirredfor 4.5 hours at 60° to 65° C., diluted with cold water and adjusted topH 3 with 1 N-hydrochloric acid. The solution was washed with ethylacetate, evaporated to remove ethyl acetate and subjected to columnchromatography on a non ionic adsorption resin "Diaion HP-20"(Trademark: Prepared by Mitsubishi Chemical Industries) (450 ml). Afterthe column was washed with water, the elution was carried out with 20%aqueous methanol. The eluates containing an object compound werecollected, evaporated to remove methanol under reduced pressure andlyophilized to give sodium7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(2-sulfonatoethyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate(syn isomer) (2.3 g), mp 165° to 171° C. (dec.).

I.R. (Nujol): 3500-3200, 1765, 1660, 1630, 1610, 1520 cm⁻¹

N.M.R. (D₂ O, δ): 1.32 (3H, t, J=7 Hz), 3.16 and 3.69 (2H, ABq, J=19Hz), 3.37 (4H, s), 4.34 (2H, q, J=7 Hz), 5.27 (1H, d, J=5 Hz), 5.28 and5.57 (2H, ABq, J=13 Hz), 5.84 (1H, d, J=5 Hz), 7.97 (2H, d, J=7 Hz),8.81 (2H, d, J=7 Hz)

EXAMPLE 3

To a mixture of 3-hydroxypyridine (2.32 g) and sodium iodide (15 g) informamide (15 ml) was added sodium7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanate(syn isomer) (6.0 g) at 75° C. under stirring, which was continued for2.5 hours at 80° to 82° C. The mixture was cooled to room temperatureand poured into isopropyl alcohol (150 ml). The resulting precipitateswere collected by filtration, washed with isopropyl alcohol anddiisopropyl ether and then dissolved in water (80 ml). The aqueoussolution was adjusted to pH 3 with 6 N-hydrochloric acid, washed withethyl acetate, evaporated to remove ethyl acetate and subjected tocolumn chromatography on a non ionic adsorption resin "Diaion HP-20"(160 ml). After the column was washed with water, the elution wascarried out with 30% aqueous methanol. The eluates containing an objectcompound were collected, evaporated to remove methanol under reducedpressure and lyophilized to give7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxy-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer) (0.93 g), mp 175° to 180° C. (dec.).

IR (Nujol): 3390, 3290, 3180, 3050, 1770, 1660, 1625, 1610, 1525 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.20 (3H, t, J=7 Hz), 3.17 and 3.47 (2H, ABq,J=18 Hz), 4.13 (2H, q, J=7 Hz), 5.07 (1H, d, J=5 Hz), 5.22 and 5.52 (2H,ABq, J=14 Hz), 5.70 (1H, d, J=5 Hz), 7.67-8.17 (2H, m), 8.40-8.90 (2H,m)

EXAMPLE 4 ##STR11## A mixture of 3-hydroxymethylpyridine (1.3 g) andpotassium iodide (7.95 g) in water (5.3 ml) was warmed to 60° C. understirring and sodium7-[2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanate(syn isomer) (5.32 g) was added thereto. The mixture was stirred for 5hours at 60° C. and diluted with a mixture of water (100 ml), ethylacetate (50 ml) and acetone (10 ml). The mixture was adjusted to pH 1with 6 N hydrochloric acid and the aqueous layer was separated out. Theaqueous solution was evaporated to remove acetone and ethyl acetate andsubjected to column chromatography on a non ionic adsorption resin"Diaion HP-20" (160 ml). After the column was washed with water (500ml), the elution was carried out with 40% aqueous methanol. The eluatescontaining an object compound were collected, evaporated to removemethanol under reduced pressure and lyophilized to give7-[2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer) (1.2 g), white powder, mp 160° to 165° C. (dec.).

IR (Nujol): 3260, 3170, 1770, 1655, 1610, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 1.33-2.00 (8H, m), 3.17, 3.50 (2H, ABq, J=18 Hz),4.57-4.90 (3H, m), 5.08 (1H, d, J=5 Hz), 5.30, 5.65 (2H, ABq, J=14 Hz),5.70 (1H, 2d, J=5 and 8 Hz), 8.00-8.33 (3H, m), 8.33-8.67 (1H, m),9.17-9.43 (2H, m), 9.42 (1H, d, J=8 Hz)

EXAMPLE 5

To a mixture of thiazole (2.5 ml), sodium iodide (18.0 g) and water 3 mlwas added sodium7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-cephalosporanate(syn isomer) (5.41 g) at 60° C. under stirring, which was continued forone hour at 75° C. The reaction mixture was diluted with water (50 ml),adjusted to pH 3.6 with 1 N hydrochloric acid and filtered. The filtratewas subjected to column chromatography on a non ionic adsorption resin"Diaion HP-20" (150 ml). After the column was washed with water, theelution was carried out with 20% aqueous methanol. The eluantscontaining an object compound were collected, evaporated to removemethanol under reduced pressure and lyophilized to give7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-thiazoliomethyl)-3-cephem-4-carboxylate(syn isomer) (2.3 g), mp 155° to 160° C. (dec.).

IR (Nujol): 3400-3200, 1770, 1660, 1600, 1520 cm⁻¹

NMR (D₂ O, δ): 1.30 (3H, t, J=7 Hz), 3.20 and 3.72 (2H, ABq, J=18 Hz),4.32 (2H, q, J=7 Hz), 5.25 (1H, d, J=5 Hz), 5.29 and 5.50 (2H, ABq, J=13Hz), 5.83 (1H, d, J=5 Hz), 8.19 (1H, d, J=4 Hz), 8.42 (1H, d, J=4 Hz)

EXAMPLE 6

A mixture of sodium iodide (13 g), dodecyl isonicotinate (5.8 g),7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylicacid (syn isomer) (5.12 g), water (2.6 ml) and acetonitrile (7.8 ml) wasstirred at 50° to 60° C. for 2 hours. To the reaction mixture was addeda mixture of ethyl acetate (60 ml) and water (60 ml). A resultingprecipitate was filtered and dissolved in a mixed solvent (1:1) ofchloroform and ethanol. The solution was washed with water, dried overmagnesium sulfate and concentrated to 30 ml. The resulting precipitateswere filtered, washed with ethyl acetate and dried to give7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-dodecyloxycarbonyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer) (2.2 g), mp 152° to 157° C. (dec.).

IR (Nujol): 3280, 3160, 1775, 1730, 1675, 1610, 1520 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 0.86 (3H, t, J=6 Hz), 1.0-1.9 (23H, m), 3.22 and3.58 (2H, ABq, J=18 Hz), 3.9-4.5 (4H, m), 5.12 (1H, d, J=5 Hz), 5.10 and5.76 (2H, ABq, J=14 Hz), 5.72 (1H, d, J=5 Hz), 8.52 (2H, d, J=6 Hz),9.56 (2H, d, J=6 Hz)

EXAMPLE 7

The following compound was obtained by reacting sodium7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylate(syn isomer) with 4-cyanopyridine according to similar manners to thoseof Examples 1 to 6.

7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-cyano-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 147° to 151° C. (dec.).

IR (Nujol): 3400-3100, 1780, 1670, 1610, 1530, 1040 cm⁻¹

NMR (D₂ O, δ): 1.31 (3H, t, J=7 Hz), 3.20 and 3.70 (2H, ABq, J=18 Hz),4.31 (2H, q, J=7 Hz), 5.25 (1H, d, J=5 Hz), 5.40 and 5.71 (2H, ABq, J=14Hz), 5.82 (1H, d, J=5 Hz), 8.45 (2H, d, J=6 Hz), 9.26 (2H, d, J=6 Hz)

EXAMPLE 8

The following compounds were obtained according to similar manners tothose of Examples 1 to 7.

(1)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 150° to 155° C. (dec.).

IR (Nujol): 3250, 1770, 1660, 1630, 1605, 1570, 1520 cm⁻¹

NMR (DMSO-d₆ +D₂ O,δ): 1.23 (3H, t, J=7 Hz), 3.22 and 3.58 (2H, ABq,J=18 Hz), 4.25 (2H, q, J=7 Hz), 4.90 (2H, s), 5.17 (1H, d, J=5 Hz), 5.28and 5.65 (2H, ABq, J=14 Hz), 5.80 (1H, d, J=5 Hz), 8.12 (2H, d, J=6 Hz),9.28 (2H, d, J=6 Hz)

(2)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-carboxy-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 175° to 185° C. (dec.).

IR (Nujol): 3400-3150, 1780, 1670, 1630, 1560, 1530, 1040 cm⁻¹

NMR (D₂ O, δ): 1.22 (3H, t, J=7 Hz), 3.23 and 3.63 (2H, ABq, J=18 Hz),4.13 (2H, q, J=7 Hz), 5.12 (1H, d, J=5 Hz), 5.33 and 5.65 (2H, ABq, J=14Hz), 5.80 (1H, d, J=5 Hz), 8.28 (2H, d, J=6 Hz), 9.13 (2H, d, J=6 Hz)

(3)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(3-hydroxypropyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate(syn isomer), mp 159° to 167° C. (dec.).

IR (Nujol): 3400-3100, 1770, 1670-1610, 1540 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.23 (3H, t, J=7 Hz), 1.7-2.1 (2H, m), 2.8-3.3(2H, m), 3.2-4.0 (4H, m), 4.20 (2H, q, J=7 Hz), 5.05 (1H, d, J=5 Hz),5.13 and 5.63 (2H, ABq, J=14 Hz), 5.75 (1H, d, J=5 Hz), 8.02 (2H, d, J=7Hz), 9.17 (2H, d, J=7 Hz)

(4)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-chloro-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 210° to 220° C. (dec.).

IR (Nujol): 3400-3100, 1770, 1660, 1610, 1520 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.23 (3H, t, J=7 Hz), 3.17 and 3.50 (2H, ABq,J=18 Hz), 4.15 (2H, q, J=7 Hz), 5.08 (1H, d, J=5 Hz), 5.0-5.8 (2H, m),5.73 (1H, d, J=5 Hz), 7.8-8.8 (2H, m), 9.4 (1H, m), 9.7 (1H, m)

(5)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-methyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 175° to 180° C. (dec.).

IR (Nujol): 3280, 1770, 1660, 1610, 1530, 1035 cm⁻¹

NMR (D₂ O, δ): 1.26 (3H, t, J=7 Hz), 2.50 (3H, s), 3.12 and 3.75 (2H,ABq, J=18 Hz), 4.29 (2H, q, J=7 Hz), 5.22 (1H, d, J=5 Hz), 5.20 and 5.53(2H, ABq, J=13 Hz), 5.82 (1H, d, J=5 Hz), 7.88 (1H, m), 8.35 (1H, m),8.73 (2H, m)

(6)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3,5-dimethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 165° to 175° C. (dec.).

IR (Nujol): 3400-3150, 1770, 1660, 1610, 1530 cm⁻¹

NMR (D₂ O, δ): 1.32 (3H, t, J=7 Hz), 2.50 (6H, s), 3.21 and 3.62 (2H,ABq, J=18 Hz), 4.32 (2H, q, J=7 Hz), 4.87 (1H, d, J=5 Hz), 5.0-5.6 (3H,m), 8.16 (1H, bs), 8.58 (2H, s)

(7)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-t-butoxycarbonylaminomethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 154° to 158° C. (dec.).

IR (Nujol): 3600, 1775, 1670, 1640, 1610, 1520, 1280, 1035 cm⁻¹

NMR (D₂ O, δ): 1.21 (3H, t, J=7 Hz), 1.40 (9H, s), 3.0-3.7 (2H, m), 4.13(2H, q, J=7 Hz), 4.40 (2H, broad s), 5.03 (1H, d, J=5 Hz), 4.9-5.8 (2H,m), 5.67 (1H, d, J=5 Hz), 7.90 (2H, d, J=6 Hz), 9.25 (2H, d, J=6 Hz)

(8)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-aminomethyl-1-pyridiniomethyl)-3-cephem-4-carboxylatediformate (syn isomer), mp 149° to 159° C. (dec.).

IR (Nujol): 3250, 3150, 1770, 1660, 1640, 1580, 1520, 1040 cm⁻¹

(9)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-t-butyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 169.5° to 175.0° C. (dec.).

IR (Nujol): 3280, 1770, 1670, 1630, 1610, 1530 cm⁻¹

NMR (D₂ O, δ): 1.40 (9H, s), 1.88 (3H, t, J=7 Hz), 3.13 and 3.70 (2H,ABq, J=19 Hz), 4.21 (2H, q, J=7 Hz), 5.25 and 5.56 (2H, ABq, J=14 Hz),5.28 (1H, d, J=5 Hz), 5.87 (1H, d, J=5 Hz), 8.05 (2H, d, J=7 Hz), 8.82(2H, d, J=7 Hz)

(10)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 155° to 160° C. (dec.).

IR (Nujol): 3350, 3200, 1775, 1670, 1615, 1525 cm⁻¹

NMR (DMSO-d₆, δ): 1.20-2.00 (8H, m), 3.13, 3.50 (2H, ABq, J=18 Hz),4.57-4.98 (3H, m), 5.08 (1H, d, J=5 Hz), 5.25, 5.60 (2H, ABq, J=14 Hz),5.67 (1H, 2d, J=5 and 8 Hz), 8.05 (2H, d, J=6 Hz), 8.10 (2H, bs), 9.27(2H, d, J=6 Hz), 9.40 (1H, d, J=8 Hz)

(11)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-acetyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 145° to 150° C. (dec.).

IR (Nujol): 3270, 1770, 1700, 1670, 1610, 1520 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.33-2.00 (8H, m), 2.67 (3H, s), 3.07, 3.45 (2H,ABq, J=18 Hz), 4.50-4.77 (1H, m), 5.02 (1H, d, J=5 Hz), 5.25, 5.58 (2H,ABq, J=14 Hz), 5.63 (1H, d, J=5 Hz), 8.40 (2H, d, J=6 Hz), 9.52 (2H, d,J=6 Hz)

(12)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-carboxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 165° to 170° C. (dec.).

IR (Nujol): 3350, 3200, 1775, 1720, 1670, 1620, 1525 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.30-2.00 (8H, m), 3.17, 3.52 (2H, ABq, J=18Hz), 3.93 (2H, s), 4.57-4.87 (1H, m), 5.07 (1H, d, J=5 Hz), 5.27, 5.63(2H, ABq, J=14 Hz), 5.70 (1H, d, J=5 Hz), 7.93-8.23 (1H, m), 8.37-8.63(1H, m), 9.10-9.37 (2H, m)

(13)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-hydroxyiminomethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 140° to 145° C. (dec.).

IR (Nujol): 3280, 3160, 1770, 1680, 1630, 1610, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 1.33-2.00 (8H, m), 3.23, 3.57 (2H, ABq, J=18 Hz),4.57-4.90 (1H, m), 5.12 (1H, d, J=5 Hz), 5.28, 5.65 (2H, ABq, J=14 Hz),5.73 (1H, 2d, J=5 and 8 Hz), 8.18 (2H, bs), 8.25 (2H, d, J=6 Hz), 8.42(1H, s), 9.35 (2H, d, J=6 Hz), 9.43 (1H, d, J=8 Hz)

(14)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-methyl-5-(2-hydroxyethyl)-3-thiazoliomethyl]-3-cephem-4-carboxylate(syn isomer), mp 150° to 155° C. (dec.).

IR (Nujol): 3330, 1780, 1670, 1610, 1530 cm⁻¹

NMR (DMSO-d₆, δ): 1.33-2.00 (8H, m), 2.57 (3H, s), 2.90-3.17 (2H, m),3.17-3.43 (2H, m), 3.57-3.80 (2H, m), 4.60-4.90 (1H, m), 5.07 (1H, d,J=5 Hz), 5.37 (2H,bs), 5.70 (1H, 2d, J=5 and 8 Hz), 8.17 (2H, bs), 9.43(1H, d, J=8 Hz), 10.23 (1H, s)

(15)7-[2-(2-Cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 140° to 145° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1660, 1620, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 1.8-2.5 (4H, m), 3.13, 3.50 (2H, ABq, J=18 Hz), 4.83(2H, s), 5.07 (1H, d, J=4 Hz), 5.20-5.40 (1H, m), 5.27, 5.67 (2H, ABq,J=14 Hz), 5.80 (1H, 2d, J=4 and 8 Hz), 5.87-6.20 (2H, m), 8.07 (2H, d,J=7 Hz), 8.17 (2H, s), 9.33 (2H, d, J=7 Hz), 9.47 (1H, d, J=8 Hz)

(16)7-[2-(2-Cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 143° to 148° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1660, 1610, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 1.8-2.5 (4H, m), 3.13, 3.47 (2H, ABq, J=17 Hz), 4.73(2H, s), 5.35 (1H, d, J=4 Hz), 5.17-5.40 (1H, m), 5.40-6.20 (5H, m),8.13 (2H, s), 8.0-8.30 (1H, m), 8.37-8.60 (1H, m), 9.27-9.43 (2H, m),9.47 (1H, d, J=8 Hz)

(17)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 170° to 175° C. (dec.).

IR (Nujol): 3300, 1770, 1670, 1620, 1525 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 3.20, 3.50 (2H, ABq, J=18 Hz), 4.63 (2H, s),4.73 (2H, s), 5.07 (1H, d, J=4 Hz), 5.27, 5.60 (2H, ABq, J=14 Hz), 5.87(1H, d, J=4 Hz), 7.90-8.17 (1H, m), 8.37-8.60 (1H, m), 9.0-9.3 (2H, m)

(18)7-[2-Ethoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 155° to 160° C. (dec.).

IR (Nujol): 3400-3150, 1770, 1670, 1610 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.23 (3H, t, J=7 Hz), 3.11, 3.67 (2H, ABq, J=18Hz), 4.23 (2H, q, J=7 Hz), 4.82 (4H, bs), 5.17 (1H, d, J=5 Hz), 5.30,5.73 (2H, ABq, J=13 Hz), 5.83 (1H, d, J=5 Hz), 8.17 (1H, m), 8.60 (1H,m), 9.23 (2H, m)

(19)7-[2-t-Butoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 145° to 150° C. (dec.).

IR (Nujol): 3300, 1775, 1740, 1670, 1610, 1525 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.50 (9H, s), 3.23, 3.60 (2H, ABq, J=17 Hz),4.65 (2H, s), 4.80 (2H, s), 5.13 (1H, d, J=4 Hz), 5.37, 5.67 (2H, ABq,J=14 Hz), 5.80 (1H, d, J=4 Hz), 8.23 (2H, s), 8.0-8.27 (1H, m),8.43-8.67 (1H, m), 9.30-9.50 (2H, m),

(20)7-[2-(1-Methyl-1-ethoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 155° to 160° C. (dec.).

IR (Nujol): 3400-3200, 1780, 1740, 1680 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.16 (3H, t, J=7 Hz), 1.48 (6H, s), 3.16, 3.62(2H, ABq, J=18 Hz), 4.16 (2H, q, J=7 Hz), 4.80 (2H, s), 5.14 (1H, d, J=5Hz), 5.2-5.8 (2H, m), 5.80 (1H, d, J=5 Hz), 8.20 (1H, m), 8.56 (1H, m),9.32 (2H, m)

(21)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(N-hydroxycarbamoyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate(syn isomer), mp 178° to 185° C. (dec.).

IR (Nujol): 3250, 3180, 1770, 1670, 1640, 1605, 1530 cm⁻¹

NMR (D₂ O, δ): 1.29 (3H, t, J=7 Hz), 3.20 and 3.72 (2H, ABq, J=19 Hz),4.30 (2H, q, J=7 Hz), 5.28 (1H, d, J=5 Hz), 5.37 and 5.70 (2H, ABq, J=14Hz), 5.88 (1H, d, J=5 Hz), 8.31 (2H, d, J=7 Hz), 9.13 (2H, d, J=7 Hz)

(22)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-butoxycarbonyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 154° to 159° C. (dec.).

IR (Nujol): 3300, 3160, 1775, 1728, 1670, 1605, 1525 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 0.8-2.0 (10H, m), 3.13 and 3.53 (2H, ABq, J=18Hz), 4.0-4.6 (4H, m), 5.08 (1H, d, J=5 Hz), 5.33 and 5.76 (2H, ABq, J=14Hz), 5.73 (1H, d, J=5 Hz), 8.55 (2H, d, J=6 Hz), 9.72 (2H, d, J=6 Hz)

(23)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-t-butoxycarbonyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 154° to 157° C. (dec.).

IR (Nujol): 3300, 3150, 1775, 1725, 1670, 1610, 1525 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.23 (3H, t, J=6.5 Hz), 1.60 (9H, s), 3.25 and3.63 (2H, ABq, J=18 Hz), 4.17 (2H, q, J=6.5 Hz), 5.10 (1H, d, J=5 Hz),5.30 and 5.83 (2H, ABq, J=14 Hz), 5.72 (1H, d, J=5 Hz), 8.52 (2H, d, J=6Hz), 9.68 (2H, d, J=6 Hz)

(24)7-[2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(N-butylcarbamoyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate(syn isomer), mp 161° to 162° C. (dec.).

IR (Nujol): 3270, 1775, 1655, 1610, 1560, 1530 cm⁻¹

NMR (DMSO-d₆, δ): 0.90 (3H, t, J=7 Hz), 1.20 (3H, t, J=7 Hz), 1.1-1.8(4H, m), 2.9-3.9 (4H, m), 4.15 (2H, q, J=7 Hz), 5.08 (1H, d, J=5 Hz),5.28 and 5.73 (2H, ABq, J=14 Hz), 5.72 (1H, 2d, J=5 and 8 Hz), 8.15 (2H,bs), 8.53 (2H, d, J=6 Hz), 9.48 (1H, d, J=8 Hz), 9.60 (2H, d, J=6 Hz)

(25)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(N-t-butylcarbamoyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate(syn isomer), mp 165° to 167° C. (dec.).

IR (Nujol): 3270, 1775, 1660, 1610, 1530 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.22 (3H, t, J=7 Hz), 1.42 (9H, s), 3.16 and3.50 (2H, ABq, J=18 Hz), 4.17 (2H, q, J=7 Hz), 5.08 (1H, d, J=5 Hz),5.25 and 5.68 (2H, ABq, J=14 Hz), 5.72 (1H, d, J=5 Hz), 8.47 (2H, d, J=7Hz), 9.62 (2H, d, J=7 Hz)

(26)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(N-dodecylcarbamoyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate(syn isomer), mp 176° to 177° C. (dec.).

IR (Nujol): 3270, 1770, 1655, 1610, 1540 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 0.85 (3H, t, J=5 Hz), 1.0-1.8 (23H, m), 3.18 and3.57 (2H, ABq, J=18 Hz), 3.1-3.9 (2H, m), 4.15 (2H, q, J=7 Hz), 5.0-6.0(4H, m), 8.6 (2H, bs), 9.6 (2H, bs)

(27)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-octyloxycarbonyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 155° to 158° C. (dec.).

IR (Nujol): 3270, 1775, 1735, 1680, 1615, 1520 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 0.86 (3H, t, J=6 Hz), 1.0-1.7 (15H, m), 3.25 and3.53 (2H, ABq, J=18 Hz), 3.9-4.7 (4H, m), 5.15 (1H, d, J=5 Hz ), 5.50and 5.72 (2H, ABq, J=14 Hz), 5.83 (1H, d, J=5 Hz), 8.57 (2H, d, J=6 Hz),9.62 (2H, d,J=6 Hz)

(28)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(N-octylcarbamoyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate(syn isomer), mp 181° to 183° C. (dec.).

IR (Nujol) 3250, 1770, 1655, 1610, 1565, 1550, 1530 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 0.86 (3H, t, J=6 Hz), 0.9-1.7 (15H, m), 2.9-3.6(4H, m), 4.15 (2H, q, J=6 Hz), 5.15 (1H, d, J=5 Hz), 5.15 and 5.77 (2H,ABq, J=14 Hz), 5.77 (1H, d, J=5 Hz), 8.62 (2H, d, J=6 Hz), 9.51 (2H, d,J=6 Hz)

(29)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-mesylamino-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 170° to 175° C. (dec.).

IR (Nujol): 3400, 1760, 1670, 1610, 1520, 1150 cm⁻¹

NMR (DMSO-d₆, δ): 1.17 (3H, t, J=7 Hz), 2.87 (3H, s), 3.20 and 3.47 (2H,ABq, J=16 Hz), 4.10 (2H, q, J=7 Hz), 5.10 (1H, d, J=4 Hz), 5.17 and 5.47(2H, ABq, J=14 Hz), 5.80 (1H, 2d, J=4 and 8 Hz), 7.6-8.5 (4H, m), 9.47(1H, d, J=8 Hz)

(30)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-ethoxycarbonyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 150° to 155° C. (dec.).

IR (Nujol): 3320, 3160, 1775, 1730, 1670, 1610, 1530, 1290 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.21 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz),3.12, 3.52 (2H, ABq, J=18 Hz), 4.12 (2H, q, J=7 Hz), 4.43 (2H, q, J=7Hz), 5.06 (1H, d, J=5 Hz), 5.33, 5.68 (2H, ABq, J=14 Hz), 5.71 (1H, d,J=5 Hz), 8.47 (2H, d, J=6 Hz), 9.60 (2H, d, J=6 Hz)

EXAMPLE 9

A solution of7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-t-butoxycarbonylaminomethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer) (1.23 g) in formic acid (20 ml) was stirred for 6.5 hoursat ambient temperature. The solution was evaporated to dryness underreduced pressure and the residue was dissolved in water. An insolublematerial was filtered off and the filtrate was subjected to columnchromatography on a non-ionic adsorption resin "Diaion HP-20" (50 ml).The elution was carried out with water. The eluates containing an objectcompound were collected and lyophilized to give7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-aminomethyl-1-pyridiniomethyl)-3-cephem-4-carboxylatediformate (syn isomer) (0.37 g), mp 149° to 159° C. (dec.).

IR (Nujol): 3250, 3150, 1770, 1660, 1640, 1580, 1520, 1040 cm⁻¹

NMR (D₂ O, δ): 1.22 (3H, t, J=7 Hz), 3.3-3.9 (2H, m), 4.05 (2H, broads), 4.17 (2H, q, J=7 Hz), 4.9-5.6 (2H, m), 5.06 (1H, d, J=4 Hz), 5.70(1H, d, J=4 Hz), 7.45 (2H, d, J=5 Hz), 8.26 (2H, s), 8.55 (2H, d, J=5Hz)

EXAMPLE 10

To a cold solution of phosphorus pentachloride (3.2 g) in methylenechloride (45 ml) was added2-t-butoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer) (4.2 g) at -18° C. and the mixture was stirred for 45minutes at -12° to -10° C. To the reaction mixture was added diisopropylether (150 ml) at -10° C. and the mixture was stirred for severalminutes and the resulting precipitate was collected by filtration. Onthe other hand, a mixture of7-amino-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylatedihydrochloride (4.0 g) and trimethylsilylacetamide (20 g) in methylenechloride (40 ml) was stirred for 30 minutes at room temperature andcooled to -20° C. To the cold solution was added the precipitateobtained above and the mixture was stirred for 30 minutes at -10° to -5°C. The reaction mixture was poured into an aqueous solution (100 ml) ofsodium bicarbonate (5.9 g) and stirred for 30 minutes at roomtemperature. The aqueous layer was separated out. To the aqueoussolution was added ethyl acetate and the mixture was adjusted to pH 1.5with 6 N hydrochloric acid. The aqueous layer was separated out, washedwith ethyl acetate and subjected to column chromatography on a non ionicadsorption resin "Diaion HP-20" (100 ml). After the column was washedwith water. The elution was carried out with 40% aqueous methanol. Theeluates containing an object compound were collected, evaporated toremove methanol under reduced pressure and lyophilized to give7-[2-t-butoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer) (2.2 g), mp 145° to 150° C. (dec.).

IR (Nujol): 3300, 1775, 1740, 1670, 1610, 1525 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.50 (9H, s), 3.23, 3.60 (2H, ABq, J=17 Hz),4.65 (2H, s), 4.80 (2H, s), 5.13 (1H, d, J=4 Hz), 5.37, 5.67 (2H, ABq,J=14 Hz), 5.80 (1H, d, J=4 Hz), 8.23 (2H, s), 8.0-8.27 (1H, m),8.43-8.67 (1H, m), 9.30-9.50 (2H, m).

EXAMPLE 11

The following compounds were obtained according to a similar manner tothat of Example 10.

(1)7-[12-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 160° to 165° C. (dec.).

IR (Nujol): 3300, 1770, 1660, 1610, 1520 cm⁻¹

(2) Sodium7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(2-sulfonatoethyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate(syn isomer), mp 165° to 171° C. (dec.).

IR (Nujol): 3500-3200, 1765, 1660, 1630, 1610, 1520 cm⁻¹

(3)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxy-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 175° to 180° C. (dec.).

IR (Nujol): 3390, 3290, 3180, 3050, 1770, 1660, 1625, 1610, 1525 cm⁻¹

(4)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-cyano-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 147° to 151° C. (dec.).

IR (Nujol): 3400-3100, 1780, 1670, 1610, 1530, 1040 cm⁻¹

(5)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 150° to 155° C. (dec.).

IR (Nujol): 3250, 1770, 1660, 1630, 1605, 1570, 1520 cm⁻¹

(6)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-carboxy-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 175° to 185° (dec.).

IR (Nujol): 3400-3150, 1780, 1670, 1630, 1560, 1530, 1040 cm⁻¹

(7)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(3-hydroxypropyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate(syn isomer), mp 159° to 167° C. (dec.).

IR (Nujol): 3400-3100, 1770, 1670-1610, 1540 cm⁻¹

(8)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-chloro-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 210° to 220° C. (dec.).

IR (Nujol): 3400-3100, 1770, 1660, 1610, 1520 cm⁻¹

(9)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-methyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 175° to 180° C. (dec.).

IR (Nujol): 3280, 1770, 1660, 1610, 1530, 1035 cm⁻¹

(10)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3,5-dimethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 165° to 175° C. (dec.).

IR (Nujol): 3400-3150, 1770, 1660, 1610, 1530 cm⁻¹

(11)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-t-butoxycarbonylaminomethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 154° to 158° C. (dec.).

IR (Nujol): 3600, 1775, 1670, 1640, 1610, 1520, 1280, 1035 cm⁻¹

(12)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-aminomethyl-1-pyridiniomethyl)-3-cephem-4-carboxylatediformate (syn isomer), mp 149° to 159° C. (dec.).

IR (Nujol): 3250, 3150, 1770, 1660, 1640, 1580, 1520, 1040 cm⁻¹

(13)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-t-butyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 169.5° to 175.0° C. (dec.).

IR (Nujol): 3280, 1770, 1670, 1630, 1610, 1530 cm⁻¹

(14)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 155° to 160° C. (dec.).

IR (Nujol): 3350, 3200, 1775, 1670, 1615, 1525 cm⁻¹

(15)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 160° to 165° C. (dec.).

IR (Nujol): 3260, 3170, 1770, 1655, 1610, 1520 cm⁻¹

(16)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-acetyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 145° to 150° C. (dec.).

IR (Nujol): 3270, 1770, 1700, 1670, 1610, 1520 cm⁻¹

(17)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-carboxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 165° to 170° C. (dec.).

IR (Nujol): 3350, 3200, 1775, 1720, 1670, 1620, 1525 cm⁻¹

(18)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-hydroxyiminomethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 140° to 145° C. (dec.).

IR (Nujol): 3280, 3160, 1770, 1680, 1630, 1610, 1520 cm⁻¹

(19)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-methyl-5-(2-hydroxyethyl)-3-thiazoliomethyl]-3-cephem-4-carboxylate(syn isomer), mp 150° to 155° C. (dec.).

IR (Nujol): 3300, 1780, 1670, 1610, 1530 cm⁻¹

(20)7-[2-(2-Cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 140° to 145° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1660, 1620, 1520 cm⁻¹

(21)7-[2-(2-Cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 143° to 148° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1660, 1610, 1520 cm⁻¹

(22)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 170° to 175° C. (dec.).

IR (Nujol): 3300, 1770, 1670, 1620, 1525 cm⁻¹

(23)7-[2-Ethoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 155° to 160° C. (dec.).

IR (Nujol): 3400-3150, 1770, 1670, 1610 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.23 (3H, t, J=7 Hz), 3.11, 3.67 (2H, ABq, J=18Hz), 4.23 (2H, q, J=7 Hz), 4.82 (4H, bs), 5.17 (1H, d, J=5 Hz), 5.30,5.73 (2H, ABq, J=13 Hz), 5.83 (1H, d, J=5 Hz), 8.17 (1H, m), 8.60 (1H,m), 9.23 (2H, m)

(24)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-mesylamino-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 170° to 175° C. (dec.).

IR (Nujol): 3400, 1760, 1670, 1610, 1520, 1150 cm⁻¹

(25)7-[2-(1-Methyl-1-ethoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 155° to 160° C. (dec.).

IR (Nujol): 3400-3200, 1780, 1740, 1680 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.16 (3H, t, J=7 Hz), 1.48 (6H, s), 3.16, 3.62(2H, ABq, J=18 Hz), 4.16 (2H, q, J=7 Hz), 4.80 (2H, s), 5.14 (1H, d, J=5Hz), 5.2-5.8 (2H, m), 5.80 (1H, d, J=5 Hz), 8.20 (1H, m), 8.56 (1H, m),9.32 (2H, m)

(26)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-thiazoliomethyl)-3-cephem-4-carboxylate(syn isomer), mp 155° to 160° C. (dec.).

IR (Nujol): 3400-3200, 1770, 1660, 1600, 1520 cm⁻¹

(27)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(N-hydroxycarbamoyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate(syn isomer), mp 178° to 185° C. (dec.).

IR (Nujol): 3250, 3180, 1770, 1670, 1640, 1605, 1530 cm⁻¹

(28)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-butoxycarbonyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 154° to 159° C. (dec.).

IR (Nujol): 3300, 3160, 1775, 1728, 1670, 1605, 1525 cm⁻¹

(29)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-t-butoxycarbonyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 154° to 157° C. (dec.).

IR (Nujol): 3300, 3150, 1775, 1725, 1670, 1610, 1525 cm⁻¹

(30)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(N-butylcarbamoyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate(syn isomer), mp 161° to 162° C. (dec.).

IR (Nujol): 3270, 1775, 1655, 1610, 1560, 1530 cm⁻¹

(31)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(N-t-butylcarbamoyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate(syn isomer), mp 165° to 167° C. (dec.).

IR (Nujol): 3270, 1775, 1660, 1610, 1530 cm⁻¹

(32)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-dodecyloxycarbonyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 152° to 157° C. (dec.).

IR (Nujol): 3280, 3160, 1775, 1730, 1675, 1610, 1520 cm⁻¹

(33)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(N-dodecylcarbamoyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate(syn isomer), mp 176° to 177° C. (dec.).

IR (Nujol): 3270, 1770, 1655, 1610, 1540 cm⁻¹

(34)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-octyloxycarbonyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 155° to 158° C. (dec.).

IR (Nujol): 3270, 1775, 1735, 1680, 1615, 1520 cm⁻¹

(35)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(N-octylcarbamoyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate(syn isomer), mp 181° to 183° C. (dec.).

IR (Nujol): 3250, 1770, 1655, 1610, 1565, 1550, 1530 cm⁻¹

(36)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-ethoxycarbonyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 150° to 155° C. (dec.).

IR (Nujol): 3320, 3160, 1775, 1730, 1670, 1610, 1530, 1290 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.21 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz),3.12, 3.52 (2H, ABq, J=18 Hz), 4.12 (2H, q, J=7 Hz), 4.43 (2H, q, J=7Hz), 5.06 (1H, d, J=5 Hz), 5.33, 5.68 (2H, ABq, J=14 Hz), 5.71 (1H, d,J=5 Hz), 8.47 (2H, d, J=6 Hz), 9.60 (2H, d, J=6 Hz)

EXAMPLE 12

To a cold mixture of trifluoroacetic acid (14 ml) and anisole (2.5 ml)was added7-[2-t-butoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer) (2.0 g) under stirring and the mixture was stirred for 80minutes at room temperature. The mixture was evaporated to removetrifluoroacetic acid and the residue was triturated with isopropylalcohol to give a powder. The powder was dissolved in water. The aqueoussolution was subjected to a column chromatography on a non ionicadsorption resin "Diaion HP-20" (100 ml). After the column was washedwith water, the elution was carried out with 15% aqueous methanol. Theeluates containing an object compound were collected, evaporated toremove methanol under reduced pressure and lyophilized to give7-[2-carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer) (1.05 g), mp 170° to 175° C. (dec.).

IR (Nujol): 3300, 1770, 1670, 1620, 1525 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 3.20, 3.50 (2H, ABq, J=18 Hz), 4.63 (2H, s),4.73 (2H, s), 5.07 (1H, d, J=4 Hz), 5.27, 5.60 (2H, ABq, J=14 Hz),5.87(1H, d, J=4 Hz), 7.90-8.17 (1H, m), 8.37-8.60 (1H, m), 9.0-9.3 (2H,m)

Preparation 13

To a solution of phosphorus pentachloride (54.6 g) in methylene chloride(500 ml) was added 2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer) (54.0 g) under stirring and cooling at -20° C. Themixture was stirred for 30 minutes at -15° to -12° C. and for 2 hours at-5° C. To the mixture containing precipitates of an object compound wasadded diisopropyl ether (500 ml) at -5° C. and the mixture was stirredfor 30 minutes at -5° to 10° C. The resulting precipitates werecollected by filtration, washed with diisopropyl ether and dried to give2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetyl chloridehydrochloride (syn isomer) (60.17 g), mp. 125° to 127° C. (dec.).

I.R. (Nujol): 1785, 1625, 1055 cm⁻¹

    ______________________________________                                        Analysis for C.sub.6 H.sub.8 O.sub.2 N.sub.4 SCl.sub.2                        C             H      N          S    Cl                                       ______________________________________                                        calc≡d:                                                                         26.57     2.95   20.66    11.81                                                                              26.20                                  found:  26.13     2.99   20.49    11.77                                                                              26.41                                  ______________________________________                                    

Preparation 14

To a suspension of diphenylmethyl7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride (27 g) inmethylene chloride (300 ml) was added N,N-dimethylaniline (36.2 g) undercooling in an ice bath at 5° C. To the solution was added portionwise2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetyl chloridehydrochloride (syn isomer) (16.2 g) below 11° C. and the mixture wasstirred for 45 minutes at 5° C. The reaction mixture was diluted with amixed solvent of methylene chloride (100 ml) and water (200 ml) andadjusted to pH 2 with 1 N hydrochloric acid. The organic layer wasseparated out, washed with water, dried over magnesium sulfate andevaporated in dryness. The residue was triturated in diethyl ether togive diphenylmethyl7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate(syn isomer) (32.4 g), mp. 120° to 125° C. (dec.).

I.R. (Nujol): 3300, 3150, 1780, 1725, 1675, 1625, 1530, 1495 cm⁻¹

N.M.R. (DMSO-d₆, δ): 1.28 (3H, t, J=7 Hz), 3.68 (2H, broad s), 4.23 (2H,q, J=7 Hz), 4.47 (2H, s), 5.27 (1H, d, J=5 Hz), 5.97 (1H, 2d, J=5 and 8Hz), 7.0 (1H, s), 7.2-7.7 (10H, m), 8.17 (2H, broad s), 9.62 (1H, d, J=8Hz)

Preparation 15

To a cold solution of diphenylmethyl7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate(syn isomer) (10 g) in a mixed solution of methylene chloride (100 ml)and acetic acid (10 ml) were added 30% hydrogen peroxide (1.84 ml) andsodium tungstate (0.3 g).

The mixture was stirred for 45 minutes in an ice bath and poured intodiethyl ether (300 ml). The precipitates were collected by filtrationand washed with diethyl ether to give diphenylmethyl7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate-1-oxide(syn isomer) (8.9 g), mp 150° to 155° C. (dec.).

I.R. (Nujol): 3280, 3170, 1785, 1723, 1667, 1628, 1530 cm⁻¹

N.M.R. (DMSO-d₆, δ): 1.30 (3H, t, J=7 Hz), 3.90 (2H, broad s), 4.23 (2H,q, J=7 Hz), 4.58 (2H, broad s), 5.12 (1H, d, J=5 Hz), 6.10 (1H, 2d, J=5and 8 Hz), 7.02 (1H, s), 7.20-7.73 (10H, m), 8.15 (2H, broad s), 9.00(1H, d, J=8 Hz)

Preparation 16

To a cold solution of diphenylmethyl7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate-1-oxide(syn isomer) (9.85 g) in acetone (222 ml) was added sodium iodide (8.22g) and the mixture was stirred for 2 hours under cooling in an ice bath.The solvent was evaporated under reduced pressure and the residue wasdissolved in a mixture of methylene chloride (200 ml) and water (100ml). The organic layer was separated out, washed with an aqueoussolution of sodium thiosulfate and water successively, dried overmagnesium sulfate and evaporated to dryness. The residue was trituratedin diethyl ether to give diphenylmethyl7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate-1-oxide(syn isomer) (10.39 g), mp. 159° to 163° C. (dec.).

I.R. (Nujol): 3250, 3150, 1780, 1720, 1670, 1620, 1520 cm⁻¹

N.M.R. (DMSO-d₆, δ): 1.29 (3H, t, J=7 Hz), 3.95 (2H, m), 4.25 (2H, q,J=7 Hz), 4.50 (2H, m), 5.12 (1H, d, J=5 Hz), 6.05 (1H, 2d, J=5 and 9Hz), 7.00 (1H, s), 7.4 (10H, m), 8.13 (2H, broad s), 8.96 (1H, d, J=9Hz)

Preparation 17 ##STR12##

A mixture of diphenylmethyl7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate-1-oxide(syn isomer) (5.0 g) and 3-aminopyridine (0.717 g) in tetrahydrofuran(35 ml) was stirred for one hour at room temperature. The resultingprecipitates were collected by filtration, washed with tetrahydrofuranand diethyl ether and dried to give diphenylmethyl7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-3-(3-amino-1-pyridiniomethyl)-3-cephem-4-carboxylate-1-oxideiodide (syn isomer) (5.41 g), mp. 157° to 162° C. (dec.).

I.R. (Nujol): 3400-3200, 1795, 1725, 1680, 1610, 1530, 1510, 1035, 705cm⁻¹

N.M.R. (DMSO-d₆, δ): 1.26 (3H, t, J=7 Hz), 3.3-4.0 (2H, m), 4.19 (2H, q,J=7 Hz), 5.08 (1H, d, J=5 Hz), 5.35 (2H, broad s), 6.10 (1H, 2d, J=5 and8 Hz), 6.6 (2H, m), 6.92 (1H, s), 7.1-7.7 (12H, m), 7.9 (2H, m), 8.03(2H, broad s), 8.93 (1H, d, J=8 Hz)

Preparation 18

To a mixture of diphenylmethyl7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-amino-1-pyridiniomethyl)-3-cephem-4-carboxylate-1-oxideiodide (syn isomer) (4.50 g) and N,N-dimethylaniline (1.34 g) inacetonitrile (45 ml) was dropped phosphorus trichloride (1.52 g) below8° C. under stirring and cooling in an ice bath. The mixture was stirredfor 70 minutes at the same temperature and diethyl ether (50 ml) wasadded thereto. The resulting precipitates were collected by filtration,washed with diethyl ether and dried to give diphenylmethyl7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-amino-1-pyridiniomethyl)-3-cephem-4-carboxylateiodide (syn isomer) (5.05 g), mp 85° to 95° C. (dec.).

I.R. (Nujol): 3300, 3200, 1790, 1680, 1630, 1510, 1220, 1185 cm⁻¹

N.M.R. (DMSO-d₆ +D₂ O, δ): 1.23 (3H, t, J=7 Hz), 3.2-3.8 (2H, m), 4.13(2H, q, J=7 Hz), 5.0-5.8 (4H, m), 6.87 (1H, s), 7.1-7.8 (12H, m),7.8-8.1 (2H, m)

Preparation 19

A solution of diphenylmethyl7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-amino-1-pyridiniomethyl)-3-cephem-4-carboxylateiodide (syn isomer) (4.9 g) in a mixed solvent (12 ml) of acetone andmethanol (1:1) was subjected to a column packed with an ion-exchangeresin [Amberlite IRA-400 (Trademark: prepared by Rohm & Haas Co.)trifluoroacetate-form] (50 ml). The elution was carried out with thesame solvent (100 ml) and the eluate was evaporated to dryness. Theresidue was triturated in diethyl ether to give diphenylmethyl7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-amino-1-pyridiniomethyl)-3-cephem-4-carboxylatetrifluoroacetate (syn isomer) (3.72 g), mp. 125° to 130° C. (dec.).

I.R. (Nujol): 3300, 3200, 1790, 1690-1620, 1510, 1200, 1180, 1035 cm⁻¹

N.M.R. (DMSO-d₆, δ): 1.25 (3H, t, J=7 Hz), 3.2-3.7 (2H, m), 4.19 (2H, q,J=7 Hz), 5.1-5.5 (2H, m), 5.29 (1H, d, J=5 Hz), 6.00 (1H, 2d, J=5 and 8Hz), 6.91 (1H, s), 7.1-7.7 (12H, m), 7.8-8.3 (4H, m), 9.73 (1H, d, J=8Hz)

EXAMPLE 13

A mixture of diphenylmethyl7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-amino-1-pyridiniomethyl)-3-cephem-4-carboxylatetrifluoroacetate (syn isomer) (500 mg) and anisole (1.0 ml) intrifluoroacetic acid (3 ml) was stirred for 35 minutes under cooling inan ice-salt bath. The mixture was poured into cold diisopropyl ether (20ml) under stirring and resulting precipitates were collected byfiltration. The powder was suspended in water (18 ml), adjusted to pH 4to 5 with aqueous solution of sodium bicarbonate and an insolublematerial was filtered off. The filtrate was subjected to columnchromatography on a non ionic adsorption resin "Diaion HP 20"(Trademark: Prepared by Mitsubishi Chemical Industries) (20 ml). Afterthe column was washed with water, the elution was carried out with 20%aqueous methanol. The eluates containing an object compound werecollected, evaporated to remove methanol under reduced pressure andlyophilized to give7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-amino-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer) (100 mg), mp. 175° to 180° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1660-1590, 1510, 1150, 1035 cm⁻¹

N.M.R. (DMSO-d₆, δ): 1.24 (3H, t, J=7 Hz), 3.04 and 3.53 (2H, ABq, J=18Hz), 4.16 (2H, q, J=7 Hz), 5.06 and 5.61 (2H, ABq, J=14 Hz), 5.10 (1H,d, J=5 Hz), 5.73 (1H, 2d, J=5 and 8 Hz), 6.6-7.2 (2H, m), 7.7 (2H, m),8.22 (2H, broad s), 8.5-8.6 (2H, m), 9.51 (1H, d, J=8 Hz)

EXAMPLE 14

The following compounds were obtained according to a similar manner tothat of Example 13.

(1)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp. 160° to 165° C. (dec.).

I.R. (Nujol): 3300, 1770, 1660, 1610, 1520 cm⁻¹

(2) Sodium7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(2-sulfonatoethyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate(syn isomer), mp. 165° to 171° C. (dec.).

I.R. (Nujol): 3500-3200, 1765, 1660, 1630, 1610, 1520 cm⁻¹

(3)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxy-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp. 175° to 180° C. (dec.).

I.R. (Nujol): 3390, 3290, 3180, 3050, 1770, 1660, 1625, 1610, 1525 cm⁻¹

(4)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-cyano-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp. 147° to 151° C. (dec.).

I.R. (Nujol): 3400-3100, 1780, 1670, 1610, 1530, 1040 cm⁻¹

(5)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp. 150° to 155° C. (dec.).

I.R. (Nujol): 3250, 1770, 1660, 1630, 1605, 1570, 1520 cm⁻¹

(6)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-carboxy-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 175° to 185° C. (dec.).

I.R. (Nujol): 3400-3150, 1780, 1670, 1630, 1560, 1530, 1040 cm⁻¹

(7)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(3-hydroxypropyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate(syn isomer), mp. 159° to 167° C. (dec.).

I.R. (Nujol): 3400-3100, 1770, 1670-1610, 1540 cm⁻¹

(8)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-chloro-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp. 210° to 220° C. (dec.).

I.R. (Nujol): 3400-3100, 1770, 1660, 1610, 1520 cm⁻¹

(9)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-methyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp. 175° to 180° C. (dec.).

I.R. (Nujol): 3280, 1770, 1660, 1610, 1530, 1035 cm⁻¹

(10)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3,5-dimethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp. 165° to 175° C. (dec.).

I.R. (Nujol): 3400-3150, 1770, 1660, 1610, 1530 cm⁻¹

(11)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-aminomethyl-1-pyridiniomethyl)-3-cephem-4-carboxylatediformate (syn isomer), mp. 149° to 159° C. (dec.).

I.R. (Nujol): 3250, 3150, 1770, 1660, 1640, 1580, 1520, 1040 cm⁻¹

(12)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-t-butyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp. 169.5° to 175.0° C. (dec.).

I.R. (Nujol): 3280, 1770, 1670, 1630, 1610, 1530 cm⁻¹

(13)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp. 155° to 160° C. (dec.).

I.R. (Nujol): 3350, 3200, 1775, 1670, 1615, 1525 cm⁻¹

(14)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp. 160° to 165° C. (dec.).

I.R. (Nujol): 3260, 3170, 1770, 1655, 1610, 1520 cm⁻¹

(15)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-acetyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp. 145° to 150° C. (dec.).

I.R. (Nujol): 3270, 1770, 1700, 1670, 1610, 1520 cm⁻¹

(16)7-[2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-carboxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp. 165° to 170° C. (dec.).

I.R. (Nujol): 3350, 3200, 1775, 1720, 1670, 1620, 1525 cm⁻¹

(17)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-hydroxyiminomethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp. 140° to 145° C. (dec.).

I.R. (Nujol): 3280, 3160, 1770, 1680, 1630, 1610, 1520 cm⁻¹

(18)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-methyl-5-(2-hydroxyethyl)-3-thiazoliomethyl]-3-cephem-4-carboxylate(syn isomer), mp. 150° to 155° C. (dec.).

I.R. (Nujol): 3330, 1780, 1670, 1610, 1530 cm⁻¹

(19)7-[2-(2-Cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp. 140° to 145° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1660, 1620, 1520 cm⁻¹

(20)7-[2-(2-Cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp. 143° to 148° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1660, 1610, 1520 cm⁻¹

(21)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp. 170° to 175° C. (dec.).

I.R. (Nujol): 3300, 1770, 1670, 1620, 1525 cm⁻¹

(22)7-[2-Ethoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp. 155° to 160° C. (dec.).

I.R. (Nujol): 3400-3150, 1770, 1670, 1610 cm⁻¹

(23)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-mesylamino-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp. 170° to 175° C. (dec.).

I.R. (Nujol): 3400, 1760, 1670, 1610, 1520, 1150 cm⁻¹

(24)7-[2-(1-methyl-1-ethoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp. 155° to 160° C. (dec.).

I.R. (Nujol): 3400-3200, 1780, 1740, 1680 cm⁻¹

(B 25)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-thiazoliomethyl)-3-cephem-4-carboxylate(syn isomer), mp. 155° to 160° C. (dec.).

I.R. (Nujol): 3400-3200, 1770, 1660, 1600, 1520 cm⁻¹

(26)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(N-hydroxycarbamoyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate(syn isomer), mp. 178° to 185° C. (dec.).

I.R. (Nujol): 3250, 3180, 1770, 1670, 1640, 1605, 1530 cm⁻¹

(27)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-butoxycarbonyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp. 154° to 159° C. (dec.).

I.R. (Nujol): 3300, 3160, 1775, 1728, 1670, 1605, 1525 cm⁻¹

(28)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(N-butylcarbamoyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate(syn isomer), mp. 161° to 162° C. (dec.).

I.R. (Nujol): 3270, 1775, 1655, 1610, 1560, 1530 cm⁻¹

(29)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(N-t-butylcarbamoyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate(syn isomer), mp. 165° to 167° C. (dec.).

I.R. (Nujol): 3270, 1775, 1660, 1610, 1530 cm⁻¹

(30)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-dodecyloxycarbonyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp. 152° to 157° C. (dec.).

I.R. (Nujol): 3280, 3160, 1775, 1730, 1675, 1610, 1520 cm⁻¹

(31)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(N-dodecylcarbamoyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate(syn isomer), mp. 176° to 177° C. (dec.).

I.R. (Nujol): 3270, 1770, 1655, 1610, 1540 cm⁻¹

(32)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-octyloxycarbonyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp. 155° to 158° C. (dec.).

I.R. (Nujol): 3270, 1775, 1735, 1680, 1615, 1520 cm⁻¹

(33)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(N-octylcarbamoyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate(syn isomer), mp. 181° to 183° C. (dec.).

I.R. (Nujol): 3250, 1770, 1655, 1610, 1565, 1550, 1530 cm⁻¹

(34)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-ethoxycarbonyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp. 150° to 155° C. (dec.).

I.R. (Nujol): 3320, 3160, 1775, 1730, 1670, 1610, 1530, 1290 cm⁻¹

EXAMPLE 15

The following compounds were obtained according to similar manners tothose of aforesaid Examples.

(1)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-amino-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp. 175° to 180° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1660-1590, 1510, 1150, 1035 cm⁻¹

(2)7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-hexadecyloxycarbonyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp. 161° to 166° C. (dec.).

I.R. (Nujol): 3400, 3250, 1770, 1730, 1670, 1610, 1520, 1285, 1120, 1035cm⁻¹

N.M.R. (DMSO-d₆ +D₂ O, δ): 0.83 (3H, t, J=7 Hz), 1.0-1.7 (29H, m),3.2-3.8(2H, m), 4.0-4.5 (4H, m), 4.9-5.3 (2H, m), 5.5-6.0(2H, m), 8.4(2H, m), 9.4 (2H, m)

Preparation 20

The following compound was obtained according to a similar manner tothat of Preparation 3. Hexadecyl isonicotinate, mp. 60° to 63° C.

I.R. (Nujol): 1722, 1560, 1480, 1410, 1290, 1275 cm⁻¹

N.M.R. (DMSO-d₆, δ): 0.7-1.8 (31H, m), 4.30 (2, t, J=5 Hz), 7.7 (2H, m),8.7 (2H, m)

What we claim is:
 1. Cephem compounds of the formula: ##STR13## whereinR¹ is amino or a protected amino group;R² is hydrogen, lower aliphatichydrocarbon group which may be substituted with one substituent selectedfrom the group consisting of carboxy, protected carboxy and halogen,cyclo(lower)alkyl or cyclo(lower)alkenyl; and R³ is a thiazolio groupwhich may be substituted with 1 to 3 substituents selected from thegroup consisting of lower alkyl and hydroxy(lower)alkyl, or a pyridiniogroup substituted with 1 to 3 substituents selected from the groupconsisting of halogen, cyano, hydroxy, amino, acylamino, lower alkanoyl,hydroxycarbamoyl, C₁ -C₁₄ L alkylcarbamoyl, carboxy, protected carboxy,lower alkyl, hydroxy(lower)alkyl, sulfo(lower)alkyl, protectedamino(lower)alkyl, amino(lower)alkyl, carboxy(lower)alkyl andhydroxyimino(lower)alkyl; and pharmaceutically acceptable salts thereof.2. Syn isomer of a compound of claim
 1. 3. A compound of claim 2,whereinR¹ is amino; R² is lower aliphatic hydrocarbon group which may besubstituted with one substituent selected from the group consisting ofcarboxy and protected carboxy, cyclo(lower)alkyl or cyclo(lower)alkenyl;and R³ is a thiazolio group which may be substituted with 1 to 3substituent(s) selected from the group consisting of lower alkyl andhydroxy(lower)alkyl or a pyridinio group substituted with 1 to 3substituent(s) selected from the group consisting of halogen, cyano,hydroxy, amino, acylamino, lower alkanoyl, hydroxycarbamoyl, C₁ -C₁₄alkylcarbamoyl, carboxy, protected carboxy, lower alkyl,hydroxy(lower)alkyl, sulfo(lower)alkyl, protected amino(lower)alkyl,amino(lower)alkyl, carboxy(lower)alkyl and hydroxyimino(lower)alkyl. 4.A compound of claim 3, whereinR² is lower alkyl which may be substitutedwith 1 substituent selected from the group consisting of carboxy andprotected carboxy, cyclo(lower)alkyl or cyclo(lower)alkenyl.
 5. Acompound of claim 4, whereinR² is lower alkyl or cyclo(lower)alkyl andR³ is a thiazolio group which may be substituted with one lower alkyland one hydroxy(lower)alkyl.
 6. A compound of claim 5, whereinR² isethyl or cyclopentyl and R³ is a thiazolio group or a thiazolio groupsubstituted with one methyl and one hydroxyethyl.
 7. A compound of claim6, which is selected from the group consistingof:7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-thiazoliomethyl)-3-cephem-4-carboxylate(syn isomer) and7-[2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-methyl-5-(2-hydroxyethyl)-3-thiazoliomethyl]-3-cephem-4-carboxylate(syn isomer).
 8. A compound of claim 4, whereinR³ is a pyridinio groupsubstituted with 1 to 2 substituent(s) selected from the groupconsisting of halogen, cyano, hydroxy, amino, lower alkanesulfonylamino,lower alkanoyl, hydroxycarbamoyl, C₁ -C₁₄ alkylcarbamoyl, carboxy,alkoxycarbonyl, lower alkyl, hydroxy(lower)alkyl, sulfo(lower)alkyl,lower alkoxycarbonylamino(lower)alkyl, amino(lower)alkyl,carboxy(lower)alkyl and hydroxyimino(lower)alkyl.
 9. A compound of claim8, whereinR² is ethyl, carboxymethyl, ethoxycarbonylmethyl,t-butoxycarbonylmethyl, 1-methyl-1-ethoxycarbonylethyl, cyclopentyl or2-cyclopenten-1-yl and R³ is a pyridinio group substituted with 1 to 2substituent(s) selected from the group consisting of chloro, cyano,hydroxy, amino, mesylamino, acetyl, hydroxycarbamoyl, butylcarbamoyl,t-butylcarbamoyl, octylcarbamoyl, dodecylcarbamoyl, carboxy,ethoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl octyloxycarbonyl,dodecyloxycarbonyl, hexadecyloxycarbonyl, methyl, t-butyl,hydroxymethyl, 3-hydroxypropyl, 2-sulfoethyl,t-butoxycarbonylaminomethyl, aminomethyl, carboxymethyl andhydroxyiminomethyl.
 10. A compound of claim 9, which is selected fromthe group consistingof:7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer),7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer),7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-cyano-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer),7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-aminomethyl-1-pyridiniomethyl)-3-cephem-4-carboxylatediformate (syn isomer),7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-chloro-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer),7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3,5-dimethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer),7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-t-butyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer),7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-methyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer),7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxy-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer),7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(3-hydroxypropyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate(syn isomer), sodium7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(2-sulfonatoethyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate(syn isomer),7-[2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer),7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-dodecyloxycarbonyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer),7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-carboxy-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer),7-[2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer),7-[2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-acetyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer),7-[2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-carboxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer),7-2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-hydroxyiminomethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer),7-[2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer),7-[2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer),7-[2-carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer),7-[2-ethoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer),7-[2-(1-methyl-1-ethoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-hydroxymethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer),7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(N-hydroxycarbamoyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate(syn isomer),7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-butoxycarbonyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer),7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-t-butoxycarbonyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer),7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(N-butylcarbamoyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate(syn isomer),7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(N-t-butylcarbamoyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate(syn isomer),7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(N-dodecylcarbamoyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate(syn isomer),7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-amino-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer),7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-octyloxycarbonyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer),7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[4-(N-octylcarbamoyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate(syn isomer),7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-mesylamino-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer),7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-ethoxycarbonyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), and7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-hexadecyloxycarbonyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer).
 11. A compound of the formula: ##STR14## wherein R¹ isamino or a protected amino;R² is hydrogen, lower aliphatic hydrocarbongroup which may be substituted with one substituent selected from thegroup consisting of carboxy, protected carboxy and halogen,cyclo(lower)alkyl or cyclo(lower)alkenyl; R⁵ is a protected carboxygroup; R⁶ is a thiazolio group which may be substituted with 1 to 3substituents selected from the group consisting of lower alkyl andhydroxy(lower)alkyl, or a pyridinio group substituted with 1 to 3substituents selected from the group consisting of halogen, cyano,hydroxy, amino, acylamino, lower alkanoyl, hydroxycarbamoyl, C₁ -C₁₄alkylcarbamoyl, carboxy, protected carboxy, lower alkyl,hydroxy(lower)alkyl, sulfo(lower)alkyl, protected amino(lower)alkyl,amino(lower)alkyl,carboxy(lower)alkyl and hydroxyimino(lower)alkyl; andY is --S-- or ##STR15## and salts thereof.
 12. A pharmaceuticalantibacterial composition comprising an effective amount of a compoundof claim 1 in association with a pharmaceutically acceptable,substantially non-toxic carrier or excipient.